Thiadiazoline derivative

ABSTRACT

(wherein R 1  and R 4  are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, or the like; R 6  represents a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, or the like; R 2  represents —C(═W)R 4  or the like; R 3  represents a hydrogen atom, —C(=W A )R 6A , or the like) 
     Antitumor agents which comprises a thiadiazoline derivative represented by the aforementioned general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 12/098,736,filed Apr. 7, 2008, which is a divisional of application Ser. No.10/497,531, which is a National Stage Application of InternationalApplication No. PCT/JP02/12961, filed Dec. 11, 2002, which was notpublished in English under PCT Article 21(2), entering the NationalStage on Jun. 10, 2004, and which claims priority of JapaneseApplication Nos. 2001-377456, filed Dec. 11, 2001 and 2002-237399, filedAug. 16, 2002. The entire disclosures of application Ser. Nos.10/497,531 and 12/098,736 are considered as being part of thisapplication, and the entire disclosures of application Ser. Nos.10/497,531 and 12/098,736 are expressly incorporated by reference hereinin their entireties.

TECHNICAL FIELD

The present invention relates to an antitumor agent comprising athiadiazoline derivative or a pharmacologically acceptable salt thereofas an active ingredient, and a thiadiazoline derivative or apharmacologically acceptable salt thereof which is useful fortherapeutic treatment of a tumor.

BACKGROUND ART

In chemotherapies of cancers, a variety of anticancer agents includingantimitotic agents such as taxane and vinca alkaloid, topoisomeraseinhibitors, alkylating agents and the like have been used. These agentshave side effects such as bone marrow toxicity and neuropathy, a problemof drug resistance and the like. Therefore, novel anticancer agentswhich have improvement in the above problems have so far been desired.

It is known that thiadiazoline derivatives have inhibitory activityagainst transcription factor STAT6 activation, antagonistic action ofintegrin, and the control of insect or acarid pests (Japanese PublishedUnexamined Patent Application No. 2000-229959, WO01/56994, U.S. Pat. No.6,235,762). In addition, it is known that the derivatives haveantibacterial activity, ACE inhibitory activity and the like [J.Bangladesh Chem. Soc., Vol. 5, p. 127 (1992), WO93/22311, JapanesePublished Unexamined Patent Application No. 62-53976 (1987)].

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a thiadiazolinederivative or a pharmacologically acceptable salt thereof which isuseful for therapeutic treatment of a human malignant tumor, forexample, breast cancer, gastric cancer, ovarian cancer, colon cancer,lung cancer, brain tumor, laryngeal cancer, hematological cancer,urinary or genital tumor including bladder cancer and prostatic cancer,renal cancer, skin carcinoma, hepatic carcinoma, pancreatic cancer, auterine cancer, or the like. Another object of the present invention isto provide an antitumor agent comprising a thiadiazoline derivative or apharmacologically acceptable salt thereof as an active ingredient.

The present invention relates to the following (1) to (43).

(1) An antitumor agent which comprises a thiadiazoline derivativerepresented by the general formula (I) or a pharmacologically acceptablesalt thereof as an active ingredient

<wherein

-   R¹ and R⁴ are the same or different and each represents

a hydrogen atom, substituted or unsubstituted lower alkyl, substitutedor unsubstituted lower alkynyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted cycloalkyl, a substituted orunsubstituted heterocyclic group, or substituted or unsubstituted aryl;

-   R² represents

a hydrogen atom, substituted or unsubstituted lower alkyl, substitutedor unsubstituted lower alkynyl, substituted or unsubstituted loweralkenyl, substituted or unsubstituted cycloalkyl,

—C(═W)R⁶ [wherein

-   -   W represents        -   an oxygen atom or a sulfur atom    -   R⁶ represents        -   a hydrogen atom, substituted or unsubstituted lower alkyl,            substituted or unsubstituted lower alkenyl, substituted or            unsubstituted cycloalkyl, a substituted or unsubstituted            aryl, a substituted or unsubstituted heterocyclic group,        -   —NR⁷R⁸ (wherein            -   R⁷ and R⁸ are the same or different and each represents                -   a hydrogen atom, substituted or unsubstituted lower                    alkyl, substituted or unsubstituted lower alkenyl,                    substituted or unsubstituted cycloalkyl, substituted                    or unsubstituted aryl, or a substituted or                    unsubstituted heterocyclic group, or            -   R⁷ and R⁸ are combined together with the adjacent                nitrogen atom to form a substituted or unsubstituted                heterocyclic group),        -   —OR⁹ (wherein            -   R⁹ represents                -   substituted or unsubstituted lower alkyl,                    substituted or unsubstituted lower alkenyl,                    substituted or unsubstituted cycloalkyl, or                    substituted or unsubstituted aryl) or        -   —SR¹⁰ (wherein            -   R¹⁰ represents                -   substituted or unsubstituted lower alkyl,                    substituted or unsubstituted lower alkenyl, or                    substituted or unsubstituted aryl)]

—NR¹¹R¹² (wherein

-   -   R¹¹ and R¹² are the same or different and each represents        -   a hydrogen atom, substituted or unsubstituted lower alkyl,            substituted or unsubstituted lower alkenyl, substituted or            unsubstituted cycloalkyl, or        -   —C(′O)R¹³ [wherein            -   R¹³ represents                -   substituted or unsubstituted lower alkyl,                    substituted or unsubstituted lower alkenyl,                    substituted or unsubstituted aryl, a substituted or                    unsubstituted heterocyclic group,                -   —NR^(7A)R^(8A) (wherein R^(7A) and R^(8A) have the                    same meanings as those of the aforementioned R⁷ and                    R⁸, respectively), or                -   —OR^(9A) (wherein R^(9A) has the same meaning as                    that of the aforementioned R⁹)]) or

—SO₂R¹⁴ (wherein

-   -   R¹⁴ represents        -   substituted or unsubstituted lower alkyl, substituted or            unsubstituted lower alkenyl, substituted or unsubstituted            aryl, or a substituted or unsubstituted heterocyclic group),            or

-   R¹ and R² are combined together with the adjacent nitrogen atom to    form a substituted or unsubstituted heterocyclic group,

-   R⁶ represents

substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted lower alkenyl, substitutedor unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclicgroup, or substituted or unsubstituted aryl, or

-   R⁴ and R⁵ are combined together to represent

—(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)— {wherein

-   -   Q represents        -   a single bond, substituted or unsubstituted phenylene, or            cycloalkylene,    -   m1 and m2 are the same or different and each represents an        integer of from 0 to 4, with the proviso that m1 and m2 are not        0 at the same time,    -   R²⁸, R²⁹, R^(28A) and R^(29A) are the same or different and each        represents a hydrogen atom, substituted or unsubstituted lower        alkyl,        -   —OR³⁰ [wherein            -   R³⁰ represents                -   a hydrogen atom,                -   substituted or unsubstituted lower alkyl,                -   substituted or unsubstituted lower alkenyl,                -   'CONR³¹R³² (wherein                -    R³¹ and R³² are the same or different and each                    represents                -    a hydrogen atom, substituted or unsubstituted lower                    alkyl, a substituted or unsubstituted heterocyclic                    group, or substituted or unsubstituted aryl),                -   —SO2NR³³R³⁴ (wherein                -    R³³ and R³⁴ are the same or different and each                    represents                -    a hydrogen atom, substituted or unsubstituted lower                    alkyl, a substituted or unsubstituted heterocyclic                    group, or substituted or unsubstituted aryl), or                -   —COR³⁵ (wherein                -    R³⁵ represents                -    a hydrogen atom, substituted or unsubstituted lower                    alkyl, a substituted or unsubstituted heterocyclic                    group, or substituted or unsubstituted aryl)],        -   —NR³⁶R³⁷ [wherein            -   R³⁶ and R³⁷ are the same or different and each                represents                -   a hydrogen atom,                -   substituted or unsubstituted lower alkyl,                -   —COR³⁸ (wherein                -    R³⁸ represents                -    a hydrogen atom, substituted or unsubstituted lower                    alkyl, a substituted or unsubstituted heterocyclic                    group, substituted or unsubstituted aryl,                    substituted or unsubstituted lower alkoxy,                    substituted or unsubstituted aryloxy, amino,                    substituted or unsubstituted lower alkylamino,                    substituted or unsubstituted di(lower alkyl)amino,                    or substituted or unsubstituted arylamino), or                -   —SO₂R³⁸ (wherein                -    R³⁹ represents                -    substituted or unsubstituted lower alkyl, a                    substituted or unsubstituted heterocyclic group, or                    substituted or unsubstituted aryl)], or        -   —CO₂R⁴⁰ (wherein            -   R⁴⁰ represents                -   a hydrogen atom, substituted or unsubstituted lower                    alkyl, or substituted or unsubstituted aryl), and

when m1 or m2 is an integer of 2 or more, each R²⁸, R²⁹, R^(28A) andR^(29A) may be the same or different, respectively, and any two of R²⁸,R²⁹, R^(28A) and R^(29A) which are bound to the adjacent two carbonatoms may be combined to form a bond}, and

-   R³ represents

a hydrogen atom or

—C(═W^(A))R^(6A) (wherein W^(A) and R^(6A) have the same meanings asthose of the aforementioned W and R⁶, respectively)>.

(2) The antitumor agent according to the aforementioned (1), wherein R⁴is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl,substituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocyclic group, or substituted or unsubstituted aryl, and R⁵ issubstituted or unsubstituted cycloalkyl, a substituted or unsubstitutedheterocyclic group, or substituted or unsubstituted aryl, or R⁴ and R⁵are combined to represent —(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)—.

(3) The antitumor agent according to the aforementioned (1), wherein Itis substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl,or substituted or unsubstituted cycloalkyl.

(4) The antitumor agent according to the aforementioned (1) or (2),wherein R⁵ is substituted or unsubstituted aryl, or a substituted orunsubstituted heterocyclic group.

(5) The antitumor agent according to the aforementioned (1) or (2),wherein R⁵ is substituted or unsubstituted phenyl, or substituted orunsubstituted thienyl.

(6) The antitumor agent according to any one of the aforementioned (1)to (5), wherein R⁴ is substituted or unsubstituted lower alkyl.

(7) The antitumor agent according to the aforementioned (1), wherein R⁴and R⁵ are combined to represent—(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)—,

(8) The antitumor agent according to the aforementioned (1), wherein R⁴and R⁵ are combined to represent —(CH₂)_(m1)-Q-(CH₂)_(m2)—.

(9) The antitumor agent according to the aforementioned (7) or (8),wherein Q is substituted or unsubstituted phenylene.

(10) The antitumor agent according to any one of the aforementioned (1)to (9), wherein R¹ is a hydrogen atom, or substituted or unsubstitutedlower alkyl.

(11) The antitumor agent according to any one of the aforementioned (1)to (9), wherein R¹ is a hydrogen atom.

(12) The antitumor agent according to any one of the aforementioned (1)to (11), wherein R² is —C(═W)R⁶.

(13) The antitumor agent according to the aforementioned (12), whereinR⁶ is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl,or substituted or unsubstituted cycloalkyl.

(14) The antitumor agent according to the aforementioned (12) or (13),wherein W is an oxygen atom.

(15) The antitumor agent according to any one of the aforementioned (1)to (9), wherein R¹ and R² are combined to form a substituted orunsubstituted heterocyclic group together with the adjacent nitrogenatom.

(16) The antitumor agent according to any one of the aforementioned (1)to (15), wherein R³ is —C(′W^(A))R^(6A).

(17) The antitumor agent according to the aforementioned (16), whereinR^(6A) is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl,or substituted or unsubstituted cycloalkyl.

(18) The antitumor agent according to the aforementioned (16), whereinR^(6A) is lower alkyl.

(19) The antitumor agent according to any one of the aforementioned (16)to (18), wherein W^(A) is an oxygen atom.

(20) A thiadiazoline derivative represented by the general formula (IA)or a pharmacologically acceptable salt thereof:

{wherein R^(1A), R^(2A), R^(3A), R^(4A) and R^(5A) have the samemeanings as those of the aforementioned R¹, R², R³, R⁴ and R⁵,respectively, with the proviso that when R^(2A) and R^(2A) are the sameto be —CONHR^(8B) (wherein R^(8B) represents a substituted orunsubstituted lower alkyl, or substituted or unsubstituted aryl), and

(i) R^(4A) is a hydrogen atom, or

(ii) one of R^(4A) and R^(5A) is substituted or unsubstituted loweralkyl, then the other of R^(4A) and R^(5A) only represents substitutedor unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl,or substituted or unsubstituted lower alkynyl

[provided that

-   -   (a) when R^(1A), R^(2A) and R^(3A) are hydrogen atoms, and one        of R^(4A) and R^(5A) is methyl,        -   the other of R^(4A) and R^(5A) is not any of phenyl,            4-nitrophenyl, 4-aminophenyl, 4-bromophenyl, 3-nitrophenyl            and 4-methoxy-3-nitrophenyl,    -   (b) when R^(1A) and R^(2A) are hydrogen atoms, R^(3A) is acetyl,        -   (i) and one of R^(4A) and R^(5A) is methyl,            -   the other of R^(4A) and R^(5A) is not any of methyl,                ethyl, phenyl, 4-methoxyphenyl,                2-naphthylsulfonylmethyl, 4-bromophenylsulfonylmethyl                and 4-chlorophenylsulfonylmethyl, and        -   (ii) and R^(4A) is a hydrogen atom,            -   R^(5A) is not any of phenyl, 4-nitrophenyl,                4-chlorophenyl, 4-methoxyphenyl, 4-dimethylaminophenyl                and pyridyl,    -   (c) when R^(1A) is a hydrogen atom, R^(2A) and R^(3A) are        acetyl,        -   (i) and one of R^(4A) and R^(5A) is methyl,            -   the other of R^(4A) and R^(5A) is not any of methyl,                ethyl, propyl, butyl, hexyl, heptyl, phenyl, benzyl,                acetylmethyl, tert-butoxycarbonylmethyl,                ethoxycarbonylmethyl, 4-bromophenylsulfonylmethyl,                4-bromophenylsulfonylethyl,                4-chlorophenylsulfonylmethyl,                3,4-dichlorophenylsulfonylmethyl,                3,4-dichlorophenylsulfonylethyl,                3,4-dimethylphenylsulfonylmethyl, phenylsulfonylmethyI,                4-methylphenylsulfonylmethyl,                4-methylphenylsulfonylethyl,                4-(acetylamino)phenylsulfonylethyl,                4-bromophenylsulfonylethyl,                2-(4-methylphenylsulfonyl)-2-phenylethyl,                2-(4-methylphenylthio)-2-phenylethyl,                2-naphthylsulfonylethyl, 2-naphthylsulfonylmethyl,                phenethyl, 3-benzoyloxyphenyl,                2-oxo-2H-1-benzopyran-3-yl, 2-furyl, 5-nitro-2-furyl,                5-methyl-2-furyl, 2-thienyl, 5-chloro-2-thienyl,                3-acetoxyphenyl, 3-nitrophenyl, 4-nitrophenyl,                4-fluorophenyl, 3-acetylaminophenyl, 4-methoxyphenyl,                3-methoxyphenyl, 4-ethylphenyl, 4-methylphenyl,                4-bromophenyl, 4-nonyloxyphenyl, 4-phenyiphenyl,                3,4-dimethoxyphenyl, 1,3-benzodioxol-5-yl,                4-(benzimidazol-2-ylamino)phenyl,                4-(1-methylbenzimidazol-2-ylamino)phenyl, 3-pyridyl,                2-naphthyl,                2-acetylamino-4-acetyl-1,3,4-thiadiazolin-5-yl and                4-acetylaminophenylsulfonylmethyl,        -   (ii) and one of R^(4A) and R^(5A) is phenyl,            -   the other of R^(4A) and R^(5A) is not any of phenyl,                4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-nitrophenyl,                ethoxycarbonylmethyl, isobutyl, sec-butyl, n-butyl and                acetylaminomethyl,        -   (iii) and one of R^(4A) and R^(6A) is 2-acetoxyphenyl,            -   the other of R^(4A) and R^(5A) is not 2-phenylethenyl;        -   (iv) and R^(4A) is a hydrogen atom or 4-methoxyphenyl,            -   R^(5A) is not 4-methoxyphenyl,        -   (v) and R^(4A) is a hydrogen atom,            -   R^(5A) is not any of phenyl, 4-nitrophenyl,                4-chlorophenyl, 4-dimethylaminophenyl and pyridyl,        -   (vi) and R^(4A) and R^(5A) are combined to represent            -   —(CH₂)_(m1)-Q-(CH₂)_(m2)— (wherein m1, m2 and Q have the                same meanings as those of the aforementioned,                respectively),                -   —(CH₂)_(m1)-Q-(CH₂)_(m2)— wherein Q is a single bond                    and the sum of m1 and m2 is 5, is excluded        -   (vii) and one of R^(4A) and R^(5A) is            1,2,3-triacetoxypropyl,            -   the other of R^(4A) and R^(5A) is not                3,4-dihydro-3-oxo-2-quinoxalinyl, and        -   (viii) and one of R^(4A) and R^(5A) is ethyl,            -   the other of R^(4A) and R^(5A) is not ethyl,    -   (d) when R^(1A) and R^(4A) are hydrogen atoms, and        -   (i) R^(2A) and R^(3A) are the same to be propionyl or            benzoyl or        -   (ii) R^(2A) is propionyl and R^(3A) is acetyl,            -   R^(5A) is not phenyl,    -   (e) when R^(1A) and R^(3A) are hydrogen atoms,        -   R^(2A) is acetyl, and        -   one of R^(4A) and R^(5A) is methyl,            -   the other of R^(4A) and R^(5A) is not either of phenyl                and 3,4-dichlorophenylsulfonylethyl,    -   (f) when R^(1A) is phenyl, R^(2A) and R^(3A) are acetyl,        -   (i) and one of R^(4A) and R^(5A) is methyl,            -   the other of R^(4A) and R^(5A) is not either of                4-acetoxy-6-methyl-2-oxo-2H-pyran-3-yl and                2-oxo-2H-1-benzopyran-3-yl, and        -   (ii) and R^(4A) is phenyl,            -   R^(5A) is not phenyl,    -   (g) when R^(1A) is methyl, R^(2A) and R^(3A) are acetyl,        -   (i) and R^(4A) is a hydrogen atom,            -   R^(5A) is not phenyl,        -   (ii) and one of R^(4A) and R^(5A) is methyl,            -   the other of R^(4A) and R^(5A) is not either of                ethoxycarbonylethyl and ethoxycarbonylpropyl,    -   (h) when R^(1A), R^(2A) and R^(4A) are methyl, and        -   R^(5A) is pyridyl,            -   R^(3A) is not —COR^(c) (wherein R^(c) represents methyl,                chloromethyl, methoxy, ethoxycarbonylmethyl or                ethoxycarbonylethenyl),    -   (j) when one of R^(1A) and R^(2A) is a hydrogen atom,        -   the other of R^(1A) and R^(2A) is ethyl, and R^(3A) is a            hydrogen atom or acetyl,            -   R^(4A) and R^(5A) are not methyl at the same time,    -   (k) when R^(1A) is 4-chlorophenyl,        -   R^(2A) is a hydrogen atom, and        -   one of R^(4A) and R^(5A) is methyl,            -   the other of R^(4A) and R^(5A) is not                (1-methylbenzimidazol-2-ylamino)phenyl, and R^(3A) is                not acetyl,    -   (m) when R^(1A) is phenyl, 4-chlorophenyl, 4-methylphenyl or        -   4-methoxyphenyl,        -   R^(2A) is a hydrogen atom, and        -   R^(4A) and R^(5A) are methyl,            -   R^(3A) is not any of acetyl, 4-chlorophenoxyacetyl,                2-chlorophenoxyacetyl, 3-methylphenoxyacetyl and                phenylaminocarbonyl,    -   (n) when R^(2A) and R^(3A) are acetyl,        -   one of R^(4A) and R^(5A) is methyl,        -   (i) and the other of R^(4A) and R^(5A) is            1H-benzotriazol-1-ylmethyl,            -   R^(1A) is not any of cyclohexyl, benzyl, phenyl,                2-methylphenyl and 4-methoxyphenyl,        -   (ii) and the other of R^(4A) and R^(5A) is            2-methylbenzimidazol-1-ylmethyl or            2-ethylbenzimidazol-1-ylmethyl,            -   R^(1A) is not any of cyclohexyl, phenyl and                4-bromophenyl,    -   (o) when R^(1A) is a hydrogen atom,        -   R^(2A) is acetyl, and        -   R^(4A) and R^(5A) are methyl,            -   R^(3A) is not benzoyl,    -   (p) when one of R^(1A) and R^(2A) is hydrogen atom,        -   the other of R^(1A) and R^(2A) is methyl, and        -   R^(4A) and R^(5A) are both methyl or both ethyl,            -   R^(3A) is not any of acetyl, benzoyl, pivaloyl,                3-nitrobenzoyl, 2-fluorobenzoyl, 4-fluorobenzoyl,                2-trifluoromethylbenzoyl and 3-trifluoromethylbenzoyl,                and    -   (q) when R^(1A) is methyl,        -   R^(2A) is methylaminocarbonyl, and        -   R^(4A) and R^(5A) are both methyl or both ethyl,            -   R^(3A) is not any of acetyl, benzoyl, pivaloyl,                2-fluorobenzoyl, 4-fluorobenzoyl,                2-trifluoromethylbenzoyl, 3-trifluoromethylbenzoyl and                4-trifluoromethylbenzoyl]}.

(21) The thiadiazoline derivative according to the aforementioned (20),wherein R^(4A) is substituted or unsubstituted lower alkyl, substitutedor unsubstituted lower alkynyl, or substituted or unsubstituted loweralkenyl, R^(5A) is substituted or unsubstituted cycloalkyl, asubstituted or unsubstituted heterocyclic group, or substituted orunsubstituted aryl, or R^(4A) and R^(5A) are combined to represent—(CR²⁸R²⁹)_(m1)-Q-(CR²⁸R^(29A))_(m2)— (wherein R²⁸, R²⁹, R^(28A),R^(29A), m1, m2 and Q have the same meanings as those of theaforementioned, respectively), or the pharmacologically acceptable saltthereof.

(22) The antitumor agent according to the aforementioned (20), whereinR^(5A) is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl,or substituted or unsubstituted cycloalkyl.

(23) The thiadiazoline derivative according to the aforementioned (20)or (21), wherein R^(5A) is substituted or unsubstituted aryl, or asubstituted or unsubstituted heterocyclic group, or thepharmacologically acceptable salt thereof.

(24) The thiadiazoline derivative according to the aforementioned (20)or (21), wherein R^(5A) is substituted or unsubstituted phenyl orsubstituted or unsubstituted thienyl, or the pharmacologicallyacceptable salt thereof.

(25) The thiadiazoline derivative according to any one of theaforementioned (20) to (24), wherein R^(4A) is substituted orunsubstituted lower alkyl, or the pharmacologically acceptable saltthereof.

(26) The thiadiazoline derivative according to any one of theaforementioned (20) to (24), wherein R^(4A) is substituted lower alkyl,or the pharmacologically acceptable salt thereof.

(27) The thiadiazoline derivative according to the aforementioned (20),wherein R^(4A) and R^(5A) combine together to represent—(CR²⁸R²⁹)_(m1)-Q-(CR^(28A)R^(29A))_(m2)— (wherein R²⁸, R²⁹, R^(28A),R^(29A), m1 , m2, and Q have the same meanings as those of theaforementioned, respectively), or the pharmacologically acceptable saltthereof.

(28) The thiadiazoline derivative according to the aforementioned (20),wherein R^(4A) and R^(5A) are combined to represent—(CH₂)_(m1)-Q-(CH₂)_(m2)— (wherein m1, m2 and Q have the same meaningsas those of the aforementioned, respectively), or the pharmacologicallyacceptable salt thereof.

(29) The thiadiazoline derivative according to the aforementioned (27)or (28), wherein Q is substituted or unsubstituted phenylene, or thepharmacologically acceptable salt thereof.

(30) The thiadiazoline derivative according to any one of theaforementioned (20) to (29), wherein R^(1A) is a hydrogen atom, orsubstituted or unsubstituted lower alkyl, or the pharmacologicallyacceptable salt thereof.

(31) The thiadiazoline derivative according to any one of theaforementioned (20) to (29), wherein R^(1A) is a hydrogen atom, or thepharmacologically acceptable salt thereof.

(32) The thiadiazoline derivative according to any one of theaforementioned (20) to (31), wherein R^(2A) is —C(═W)R⁶ (wherein W andR⁶ have the same meanings as those of the aforementioned, respectively),or the pharmacologically acceptable salt thereof.

(33) The thiadiazoline derivative according to the aforementioned (32),wherein R⁶ is substituted or unsubstituted lower alkyl, substituted orunsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl,or substituted or unsubstituted cycloalkyl, or the pharmacologicallyacceptable salt thereof.

(34) The thiadiazoline derivative according to the aforementioned (32)or (33), wherein W is an oxygen atom, or the pharmacologicallyacceptable salt thereof.

(35) The thiadiazoline derivative according to any one of theaforementioned (20) to (29), wherein R^(1A) and R^(2A) are combinedtogether with the adjacent nitrogen atom to form a substituted orunsubstituted heterocyclic group, or the pharmacologically acceptablesalt thereof.

(36) The thiadiazoline derivative according to any one of theaforementioned (20) to (35), wherein R^(3A) is —C(═W^(A))R^(6A) (whereinW^(A) and R^(6A) have the same meanings as those of the aforementioned,respectively), or the pharmacologically acceptable salt thereof.

(37) The thiadiazoline derivative according to the aforementioned (36),wherein R^(6A) is substituted or unsubstituted lower alkyl, substitutedor unsubstituted lower alkynyl, substituted or unsubstituted loweralkenyl, or substituted or unsubstituted cycloalkyl, or thepharmacologically acceptable salt thereof.

(38) The thiadiazoline derivative according to the aforementioned (36),wherein R^(6A) is lower alkyl, or the pharmacologically acceptable saltthereof.

(39) The thiadiazoline derivative according to any one of theaforementioned (36) to (38), wherein W^(A) is an oxygen atom, or thepharmacologically acceptable salt thereof.

(40) A pharmaceutical composition which comprises the thiadiazolinederivative according to any one of the aforementioned (20) to (39) or apharmacologically acceptable salt thereof as an active ingredient.

(41) An antitumor agent which comprises the thiadiazoline derivativeaccording to any one of the aforementioned (20) to (39) or apharmacologically acceptable salt thereof as an active ingredient.

(42) Use of the thiadiazoline derivative according to any one of theaforementioned (20) to (39) or a pharmacologically acceptable saltthereof for the manufacture of an antitumor agent.

(43) A method for the treatment of malignant tumor comprisingadministering an effective amount of the thiadiazoline derivativeaccording to any one of the aforementioned (20) to (39) or apharmacologically acceptable salt thereof.

Hereinafter, compounds represented by the general formulae (I) and (IA)are referred to as Compound (I) and Compound (IA), respectively. Thecompounds having the other formula numbers are referred to in the samemanner.

In the definition of each group of Compound (I) and Compound (IA),

(i) examples of the lower alkyl moiety in the lower alkyl, the loweralkoxy, the lower alkylamino and the di(lower alkylamino includestraight or branched chain alkyl having 1 to 10 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl and the like.

The two lower alkyl moieties in the di(lower alkylamino may be the sameor different.

(ii) Examples of the cycloalkyl include cycloalkyl having 3 to 8 carbonatoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like.

Examples of the cycloalkylene include cycloalkylene having 3 to 8 carbonatoms, for example, cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene, cycloheptylene, cyclooctylene and the like.

(iii) Examples of the lower alkenyl include straight or branched chainalkenyl having 2 to 8 carbon atoms, for example, vinyl, allyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl and the like.

(iv) Examples of the lower alkynyl include straight or branched chainalkynyl having 2 to 8 carbon atoms, for example, ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like.

(v) Examples of the aryl moiety in the aryl, the aryloxy and thearylamino include phenyl, naphthyl and the like.

(vi) Examples of the heterocyclic group include an aliphaticheterocyclic group, an aromatic heterocyclic group and the like.Examples of the aliphatic heterocyclic group include a 5- or 6-memberedmonocyclic aliphatic heterocyclic group containing at least one atomselected from a nitrogen atom, an oxygen atom and a sulfur atom, and abicyclic or tricyclic condensed aliphatic heterocyclic group comprising3- to 8-membered rings and containing at least one atom selected from anitrogen atom, an oxygen atom and a sulfur atom, and the like, forexample, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, piperidino, morpholino, oxazolinyl,dioxolanyl, tetrahydropyranyl and the like. Examples of the aromaticheterocyclic group include a 5- or 6-membered monocycle aromaticheterocyclic group containing at least one atom selected from a nitrogenatom, an oxygen atom and a sulfur atom, and a bicycle or tricycliccondensed aromatic heterocyclic group comprising 3- to 8-membered ringsand containing at least one atom selected from a nitrogen atom, anoxygen atom and a sulfur atom, and the like, for example, furyl,thienyl, benzothienyl, pyrrolyl, pyridyl, pyrazinyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl,ozadiazolyl, pyrimidinyl, indolyl, isoindolyl, benzothiazolyl,benzimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolinyl,pyranyl and the like.

(vii) Examples of the heterocyclic group formed together with theadjacent nitrogen atom include an aliphatic heterocyclic groupcontaining at least one nitrogen atom, and the like. Said aliphaticheterocyclic group containing at least one nitrogen atom may contain anoxygen atom, a sulfur atom or another nitrogen atom, and examplesthereof include, for example, pyrrolidinyl, morpholino, thiomorpholino,pyrazolidinyl, piperidino, piperazinyl, homopiperazinyl, aziridinyl,azetidinyl, azolidinyl, perhydroazepinyl, perhydroazocinyl,succinimidyl, pyrrolidonyl, glutarimidyl, piperidonyl and the like.

(viii) The substituents in the substituted lower alkyl, the substitutedlower alkoxy, the substituted lower alkenyl, the substituted loweralkynyl, the substituted cycloalkyl, the substituted lower alkylamino,and the substituted di(lower alkylamino may be the same or different andinclude for example, 1 to 3 substituent(s), such as halogen, oxo,hydroxy, nitro, aside, cycloalkyl, aryl, a heterocyclic group,substituted aryl (the substituent in said substituted aryl has the samemeaning as that of the after-mentioned substituent (xii) in thesubstituted aryl), a substituted heterocyclic group (the substituent insaid substituted heterocyclic group has the same meaning as that of theafter-mentioned substituent (xiii) in the substituted heterocyclicgroup), —CONR¹⁵R¹⁶ <wherein

R¹⁵ and R¹⁶ are the same or different and each represents

-   -   a hydrogen atom, hydroxy, cycloalkyl, lower alkyl,    -   lower alkenyl, aryl, a heterocyclic group,    -   substituted aryl (the substituent in said substituted aryl has        the same meaning as that of the after-mentioned        substituent (xii) in the substituted aryl),    -   a substituted heterocyclic group (the substituent in said        substituted heterocyclic group has the same meaning as that of        the after-mentioned substituent (xiii) in the substituted        heterocyclic group) or    -   substituted lower alkyl {in said substituted lower alkyl, the        substituents are the same or different and 1 to 3        substituent(s), such as        -   hydroxy, lower alkoxy, oxo, carboxy,        -   lower alkoxycarbonyl, an aryl, a heterocyclic group,        -   —CONR^(15A)R^(16A) [wherein            -   R^(15A) and R^(16A) are the same or different and each                represents                -   a hydrogen atom, hydroxy, lower alkyl, or                -   substituted lower alkyl (in said substituted lower                    alkyl, the substituents (a) are the same or                    different and 1 to 3 substituent(s), such as                    hydroxy, lower alkoxy, oxo, carboxy, lower                    alkoxycarbonyl, aryl, a heterocyclic group, amino,                    lower alkylamino, di(lower alkyl)amino and the                    like), or            -   R^(15A) and R^(16A) are combined to form a heterocyclic                group            -   together with the adjacent nitrogen atom],        -   —NR⁴¹R⁴² [wherein            -   R⁴¹ and R⁴² are the same or different and each                represents                -   a hydrogen atom, lower alkyl,                -   lower alkanoyl, aroyl, aryl,                -   a heterocyclic group,                -   substituted lower alkyl (the substituent in said                    substituted lower alkyl has the same meaning as that                    of the aforementioned substituent (a) in the                    substituted lower alkyl),                -   a substituted lower alkanoyl (in said substituted                    lower alkanoyl, the substituents (b) are the same or                    different and 1 to 3 substituent(s), such as                    hydroxy, lower alkoxy, oxo, carboxy, lower                    alkoxycarbonyl, amino, lower alkylamino, di(lower                    alkyl)amino and the like),                -   substituted aroyl (the substituent in said                    substituted aroyl has the same meaning as that of                    the aforementioned substituent (b) in the                    substituted lower alkanoyl),                -   substituted aryl (the substituent in said                    substituted aryl has the same meaning as that of the                    after-mentioned substituent (xii) in the substituted                    aryl) or                -   a substituted heterocyclic group (the substituent in                    said substituted heterocyclic group has the same                    meaning as that of the after-mentioned                    substituent (xiii) in the substituted heterocyclic                    group), or            -   R⁴¹ and R⁴² are combined to form a heterocyclic group or                a substituted heterocyclic group together with the                adjacent nitrogen atom (the substituent in said                substituted heterocyclic group formed together with the                adjacent nitrogen atom has the same meaning as that of                the after-mentioned substituent (xiii) in the                substituted heterocyclic group formed together with the                adjacent nitrogen atom)]), or

R¹⁵ and R¹⁶ are combined to form a heterocyclic group or a substitutedheterocyclic group together with the adjacent nitrogen atom (thesubstituent in said substituted heterocyclic group formed together withthe adjacent nitrogen atom has the same meaning as that of theafter-mentioned substituent (xiii) in the substituted heterocyclic groupformed together with the adjacent nitrogen atom)>, —CO₂R²⁶ (wherein

R²⁶ represents

-   -   a hydrogen atom, lower alkyl, cycloalkyl, lower alkenyl,    -   lower alkynyl, aryl,    -   substituted aryl (the substituent in said substituted aryl has        the same meaning as that of the after-mentioned        substituent (xii) in the substituted aryl), or    -   substituted lower alkyl [in said substituted lower alkyl, the        substituents (c) are the same or different and 1 to 3        substituent(s), such as        -   hydroxy, halogen, lower alkoxy, oxo, carboxy,        -   lower alkoxycarbonyl, aryl, a heterocyclic group,        -   —CONR^(15B)R^(16B) (wherein R^(15B) and R^(16B) have the            same meanings as those of the aforementioned R¹⁵ and R¹⁶,            respectively),        -   —NR^(41A)R^(42A) (wherein R^(41A) and R^(42A) have the same            meanings as those of the aforementioned R⁴¹ and R⁴²,            respectively), and the like]}, —COR^(26A) (wherein R^(26A)            has the same meaning as that of the aforementioned R²⁶),

-   —NR¹⁷R¹⁸ <wherein

R¹⁷ and R¹⁸ are the same or different and each represents

-   -   a hydrogen atom, lower alkyl, lower alkenyl, aroyl,    -   aryl, a heterocyclic group, cycloalkyl,    -   aralkyloxycarbonyl,    -   substituted lower alkyl (in said substituted lower alkyl, the        substituents (d) are the same or different and 1 to 3        substituent(s), such as        -   hydroxy, lower alkoxy, oxo, carboxy,        -   lower alkoxycarbonyl, aryl, a heterocyclic group,        -   substituted aryl (the substituent in said substituted aryl            has the same meaning as that of the after-mentioned            substituent (xii) in the substituted aryl),        -   a substituted heterocyclic group (the substituent in said            substituted heterocyclic group has the same meaning as that            of the after-mentioned substituent (xiii) in the substituted            heterocyclic gram),        -   —O(CH₂CH₂O)_(n)R¹⁹ (wherein n represents an integer of from            1 to 15, and R¹⁹ represents lower alkyl),        -   —CONR^(15C)R^(16C) (wherein R^(15C) and R^(16C) have the            same meanings as those of the aforementioned R¹⁵ and R¹⁶,            respectively),        -   —SO₂R²⁴ [wherein            -   R²⁴ represents                -   lower alkyl, arylor                -   substituted aryl (the substituent in said                    substituted aryl has the same meaning as that of the                    after-mentioned substituent (xii) in the substituted                    aryl)],        -   —NR^(41B)R^(42B) (wherein R^(41B) and R^(42B) have the same            meanings as those of the aforementioned R⁴¹ and R⁴²,            respectively), and the like},    -   substituted aryl (the substituent in said substituted aryl has        the same meaning as that of the after-mentioned        substituent (xii) in the substituted aryl),    -   a substituted heterocyclic group (the substituent in said        substituted heterocyclic group has the same meaning as that of        the after-mentioned substituent (xiii) in the substituted        heterocyclic group),    -   —COR^(26B) {wherein        -   R^(26B) represents            -   lower alkyl, lower alkenyl, lower alkynyl,            -   aryl,            -   substituted lower alkyl (the substituent in said                substituted lower alkyl has the same meaning as that of                the aforementioned substituent (c) in the substituted                lower alkyl),            -   substituted aryl (the substituent in said substituted                aryl has the same meaning as that of the after-mentioned                substituent (xii) in the substituted aryl),            -   —NR^(26C)R^(26D) (wherein R^(26C) and R^(26D) are the                same or different, and each has the same meaning as-that                of the aforementioned R²⁶) or            -   —OR²⁷ [wherein                -   R²⁷ represents                -    lower alkyl, aryl,                -    substituted lower alkyl (the substituent in said                    substituted lower alkyl has the same meaning as that                    of the aforementioned substituent (c) in the                    substituted lower alkyl) or                -    substituted aryl (the substituent in said                    substituted aryl has the same meaning as that of the                    after-mentioned substituent (xii) in the substituted                    aryl)]), or    -   —SO₂R^(26E) (wherein R^(26E) has the same meaning as that of the        aforementioned R²⁶), or

R¹⁷ and R¹⁸ are combined to form a heterocyclic group or a substitutedheterocyclic group together with the adjacent nitrogen atom (thesubstituent in said substituted heterocyclic group formed together withthe adjacent nitrogen atom has the same meaning as that of theafter-mentioned substituent (xiii) in the substituted heterocyclic groupformed together with the adjacent nitrogen atom)>, —N⁺R²⁰R²¹R²²X—(wherein

R²⁰ and R²¹ are the same or different and each represents lower alkyl,or R²⁰ and R²¹ are combined to form a heterocyclic group together withthe adjacent nitrogen atom,

R²² represents lower alkyl, and

X represents each atom of chlorine, bromine or iodine),

-   —OR²³ {wherein

R²³ represents

-   -   lower alkyl, cycloalkyl, aryl, a heterocyclic group,    -   substituted aryl (the substituent in said substituted aryl has        the same meaning as that of the after-mentioned        substituent (xii) in the substituted aryl),    -   a substituted heterocyclic group (the substituent in said        substituted heterocyclic group has the same meaning as that of        the after-mentioned substituent (xiii) in the substituted        heterocyclic group),    -   substituted lower alkyl [in said substituted lower alkyl, the        substituents (e) are the same or different and 1 to 3        substituent(s), such as        -   hydroxy, halogen, lower alkoxy, oxo, carboxy,        -   lower alkoxycarbonyl, aryl, a heterocyclic group,        -   substituted aryl (the substituent in said substituted aryl            has the same meaning as that of the after-mentioned            substituent (xii) in the substituted aryl),        -   a substituted heterocyclic group (the substituent in said            substituted heterocyclic group has the same meaning as that            of the after-mentioned substituent (xiii) in the substituted            heterocyclic group),        -   —O(CH₂CH₂O)_(nA)R^(19A) (wherein nA and R^(19A) have the            same meanings as those of the aforementioned n and R¹⁹,            respectively),            -   —CONR^(15D)R^(16D) (wherein R^(15D) and R^(16D) have the                same meanings as those of R¹⁵ and R¹⁶, respectively),        -   —NR^(41C)R^(42C) (wherein R^(41C) and R^(42C) have the same            meanings as those of the aforementioned R⁴¹ and R⁴²,            respectively) and the like],    -   —COR^(26F) (wherein R^(26F) has the same meaning as that of the        aforementioned R²⁶) or    -   —CONR^(15E)R^(16E) (wherein R^(15E) and R^(16E) have the same        meanings as those of the aforementioned R¹⁵ and R¹⁶,        respectively)),

-   —SR^(23A) (wherein R^(23A) has the same meaning as that of the    aforementioned R²³), —SO₂R²⁵ [wherein

R²⁵ represents

-   -   lower alkyl, cycloalkyl, aryl,    -   substituted lower alkyl (the substituent in said substituted        lower alkyl has the same meaning as that of the aforementioned        substituent (c) in the substituted lower alkyl),    -   a substituted aryl (the substituent in the substituted aryl has        the same meaning as that of the after-mentioned        substituent (xii) in the substituted aryl), or    -   —NR^(16F)R^(16F) (wherein R^(15F) and R^(16F) have the same        meanings as those of the aforementioned R¹⁵ and R¹⁶,        respectively)],        —OSO₂R^(25A) (wherein R^(25A) has the same meaning as that of        the aforementioned R²⁵), and the like.

Herein, the lower alkyl moiety in the lower alkyl, the lower alkoxy, thelower alkoxycarbonyl, the lower alkylamino and the di(lower alkylamino,the aryl moiety in the aryl and the aroyl, the cycloalkyl, the loweralkenyl, the lower alkynyl, the heterocyclic group, and the heterocyclicgroup formed together with the adjacent nitrogen atom have the samemeanings as those of the aforementioned lower alkyl (i), aryl (v),cycloalkyl (ii), lower alkenyl (iii), lower alkynyl (iv), heterocyclicgroup (vi) and a heterocyclic group formed together with the adjacentnitrogen atom (vii), respectively. Also, the lower alkyl moiety in thelower alkanoyl mentioned here has the same meaning as that of theaforementioned lower alkyl (i), the halogen (ix) represents each atom offluorine, chlorine, bromine and iodine, and examples of the aralkylmoiety (xi) in the aralkyloxycarbonyl include aralkyl having 7 to 15carbon atoms, for example, benzyl, phenethyl, benzhydryl, naphthylmethyland the like.

(xii) The substituents in the substituted aryl, the substituted aryloxy,the substituted arylamino and the substituted phenylene may be the sameor different and 1 to 3 substituent(s), such as

halogen, lower alkyl, nitro, oxo, hydroxy, lower alkoxy, amino, loweralkylamino, di(lower alkyl)amino, lower alkylaminocarbonyloxy, di(loweralkyl)aminocarbonyloxy, lower alkanoyl, lower alkanoylamino, loweralkanoyloxy, aryl, arylsulfonyl, heterocyclic amino, aroyl, carboxy,lower alkoxycarbonyl, cyano, methylenedioxy,

substituted lower alkyl (in said substituted lower alkyl, thesubstituents (f) are the same or different and 1 to 3 substituent(s),such as halogen, oxo, carboxy, lower alkoxycarbonyl, amino, loweralkylamino, di(lower alkyl)amino, hydroxy, lower alkoxy and the like),

substituted arylsulfonyl (the substituent in said substitutedarylsulfonyl has the same meaning as that of the aforementionedsubstituent (f)),

substituted heterocyclic amino (the substituent in said substitutedheterocyclic amino has the same meaning as that of the aforementionedsubstituent (f)) and the like.

the lower alkyl moiety in the lower alkyl, the lower alkylamino, thedi(lower alkylamino, the lower alkylaminocarbonyloxy, the di(loweralkyl)aminocarbonyloxy (the two lower alkyl moieties in said di(loweralkyl)aminocarbonyloxy may be the same or different), the loweralkoxycarbonyl and the lower alkoxy, the heterocyclic moiety in theheterocyclic amino, the aryl moiety in the aryl, the arylsulfonyl andthe aroyl, and the halogen have the same meanings as those of theaforementioned lower alkyl (i), heterocyclic group (vi), aryl (v) andhalogen (ix), respectively. Also, examples of the lower alkanoyl moiety(x) in the lower alkanoyl, the lower alkanoylamino and the loweralkanoyloxy which are noted here include a straight or branched chainalkanoyl having 2 to 9 carbon atoms, for example, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,octanoyl, nonanoyl and the like.

(xiii) Examples of the substituent-in the substituted heterocyclic groupand the substituted heterocyclic group formed together with the adjacentnitrogen atom include oxo and the like as well as the aforementionedgroups mentioned in the definition of the substituent (xii) in thesubstituted aryl.

Example of the pharmacologically acceptable salt of Compound (I) andCompound (IA) include pharmacologically acceptable acid addition salts,metal salts, ammonium salts, organic amine addition salts, amino acidaddition salts and the like. Examples of the acid addition salt includean inorganic salt such as a hydrochloride, a sulfate and a phosphate, anorganic acid salt such as an acetate, a maleate, a fumarate, a tartrate,a citrate, a lactate, an aspartate, a glutamate, succinate and the like.Examples of the metal salt include an alkali metal salt such as a sodiumsalt and a potassium salt, an alkaline-earth metal salt such as amagnesium salt and a calcium salt, an aluminium salt, a zinc salt andthe like. Examples of the ammonium salt include a salt of ammonium,tetramethylammonium and the like. Examples of the organic amine additionsalt include an addition salt with morpholine, piperidine or the like.Examples of the amino acid addition salt include an addition salt withlysine, glycine, phenylalanine and the like.

Next, the methods of preparing the Compound (I) and the Compound (IA)are described as follows.

In the preparing methods as shown below, when the defined group changesunder the conditions of the method carried out, or the method isinappropriate for carrying out, the desired compound can be obtained byusing the protection and deprotection of the groups which are ordinarilyused in the synthetic organic chemistry [e.g., Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1981)] and thelike. In addition, the order of the steps for introducing a substituentand the like may be changed, if necessary.

Compound (I) can be prepared according to the following reaction steps.

Compound (IA) can also be prepared in the similar manner as in thepreparing methods of Compound (I) as shown below.

Preparing Method 1

Among Compound (I), Compound (Ia) wherein R² is a hydrogen atom,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower alkynyl, substituted or unsubstituted lower alkenyl, orsubstituted or unsubstituted cycloalkyl, or R¹ and R² are combined toform a substituted or unsubstituted heterocyclic group together with theadjacent nitrogen atom, and R³ is —C(═O)R^(6A) can be obtained fromCompound (II) and Compound (III), via Compound (IV), in accordance withknown methods [e.g., J. Heterocyclic Chem., Vol. 21, p. 599 (1984) andthe like]:

(wherein R¹, R⁴, R⁵, R⁶ and R^(6A) have the same meanings as thosementioned above, respectively, X¹ has the same meaning as that of theaforementioned X, and R^(2a) represents a hydrogen atom, substituted orunsubstituted lower alkyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted lower alkenyl, or substituted orunsubstituted cycloalkyl among the definition of the aforementioned R²,or R¹ and R^(2a) are combined to form a substituted or unsubstitutedheterocyclic group together with the adjacent nitrogen atom.)

Preparing Method 2

Among Compound (I), Compound (Ib) wherein R² and R³ are the same to be—C(═O)R^(6B) (wherein R^(6B) has the same meaning as that of theaforementioned R⁶) can be obtained from Compound (IVa) among Compound(IV) prepared by the preparing method 1 wherein R^(2a) is a hydrogenatom, and Compound (Va) or Compound (Vb) in accordance with knownmethods [e.g., J. Bangladesh Chem. Soc., Vol. 5, p. 127 (1992), J. Org.Chem., Vol. 45, p. 1473 (1980), Patent of East. Germany No. 243930, andthe like]:

(wherein R¹, R⁴, R⁵ and R^(6B) have the same meanings as those mentionedabove, respectively.)

Preparing Method 3

Among Compound (Ia), Compound (Ic) wherein R² is a hydrogen atom and R⁸is —C(═O)R^(6A) can be obtained by the following step from Compound (Ib)prepared by the Preparing method 2:

(wherein R¹, R⁴, R⁶, R^(6A) and R^(6B) have the same meanings as thosementioned above, respectively.)

Compound (Ic) can be obtained by treatment of Compound (Ib) in an inertsolvent, for example, N,N-dimethylformamide and the like, in thepresence of an appropriate base such as sodium hydride and the like, ata temperature between 0° C. and 80° C. for 10 minutes to 10 hours. Thebase is preferably used in an amount of 1 to 5 equivalents to Compound(Ib).

Alternatively, Compound (Ic) can also be obtained by the followingmethod.

Compound (Ic) can be obtained by treatment of Compound (Ib) in an inertsolvent, for example, aqueous or anhydrous ethanol, acetonitrile,chloroform and the like, in the presence of an appropriate base such ashydrazine monohydrate, aqueous sodium hydroxide and the like, at atemperature between 0° C. and 50° C. for 1 to 10 hours. The base ispreferably used in an amount of 2 to 10 equivalents to Compound (Ib).

Compound (Ic) can also be obtained by the following method.

Compound (Ic) can be obtained by treatment of Compound (Ib) in a solventsuch as methanol, tert-butanol and the like, in the presence of areducing agent such as sodium borohydride and the like, and ifnecessary, in the presence of cerium chloride heptahydrate and the like,at a temperature between −10° C. and 100° C. for 0.1 to 15 hours. Thereducing agent is preferably used in an amount of 1 to 200 equivalentsto Compound (Ib).

Preparing Method 4

Among Compound (I), Compound (Ie) wherein R² is —C(═O)R⁶ and R³ is—C(═O)R^(6A) can be obtained by the following step from Compound (Ic)obtained by the Preparing method 1 or 3.

(wherein R¹, R⁴, R⁵, R⁶ and R^(6A) have the same meanings as thosementioned above, respectively, and X² has the same meaning as that ofthe aforementioned X.)

Compound (Ie) can be obtained by allowing Compound (Ic) to react withCompound (VA) or Compound (VB) in an inert solvent, for example,acetone, ethyl acetate, acetonitrile, N,N-dimethylformamide,dichloromethane and the like, in the presence of an appropriate basesuch as pyridine, 4-(dimethylamino)pyridine (DMAP), sodium hydride andthe like, at a temperature between 0° C. and 120° C. for 2 to 12 hours.The base and Compound (VA) or Compound (VB) are preferably used,respectively, in an amount of 1 to 3 equivalents to Compound (Ic).

Preparing Method 5

Among Compound (I), Compound (If) wherein R² is —SO₂R¹⁴ and R³ is—C(═O)R^(6A) can be obtained from Compound (Ic) prepared by thePreparing method 1 or 3 in accordance with the method described in forexample, Shin-Jikken-Kagaku-Koza (New Experiment Chemistry Lecture) Vol.14, p. 1803 (Maruzen. 1978):

(wherein R¹, R⁴, R⁵, R^(6A) and R¹⁴ have the same meanings as thosementioned above, respectively, and X³ has the same meaning as that ofthe aforementioned X.)

Preparing Method 6

Among Compound (I), Compound (Ig) wherein R² is —NR¹¹R¹² and R³ is—C(═O)R^(6A) can be obtained from Compound (VII) prepared in accordancewith the method described in Indian J. Chem., Section B, Vol. 31(B), p.547 (1992) in accordance with the methods described in for example,Indian J. Chem., Section B, Vol. 31B(8), p. 547 (1992), PhosphorusSulfur & Silicon & the Related Elements, Vol. 122, p. 307 (1997) and thelike,:

(wherein R¹, R⁴, R⁵, R^(6A), R¹¹ and R¹² have the same meanings as thosementioned above, respectively.)

Preparing Method 7

Among Compound (Ie), Compound (Ie-b) wherein R¹ is substituted orunsubstituted lower alkyl, substituted or unsubstituted lower alkynyl,substituted or unsubstituted lower alkenyl, or substituted orunsubstituted cycloalkyl can be obtained by the following step fromCompound (Ie-a) among Compound (Ie) wherein R¹ is a hydrogen atomprepared by the Preparing method 4:

(wherein R⁴, R⁵, R⁶ and R^(6A) have the same meanings as those mentionedabove, respectively, X⁴ has the same meaning as that of theaforementioned X, and R^(1a) represents substituted or unsubstitutedlower alkyl,a substituted or unsubstituted lower alkynyl, substituted orunsubstituted lower alkenyl, or substituted or unsubstituted cycloalkylamong the definition of the aforementioned R¹.)

Compound (Ie-b) can be obtained by allowing Compound (Ie-a) to reactwith Compound (VIII) in an inert solvent, for example,N,N-dimethylformamide and the like, in the presence of an appropriatebase such as sodium hydroxide, at a temperature between 0° C. and roomtemperature for 1 to 24 hours. The base and Compound (VIII) arepreferably used in amounts of 2 to 5 equivalents and 2 to 3 equivalents,respectively, to Compound (Ie-a).

Preparing Method 8

Among Compound (I), Compound (Ih) wherein R³ is a hydrogen atom can beobtained by the methods described in for example, Phosphorus, Sulfur andSilicone and the Related Elements, Vol. 122, p. 307 (1997) and Chem.Ber., Vol. 123, p. 691 (1990) and the like, or the methods similar tothe aforementioned methods.

Preparing Method 9

Among Compound (I), Compound (Ij) wherein R² and/or R² is —C(═S)R⁶and/or —C(═S)R^(6A), respectively, can be obtained by thiocarbonylationof Compound (Ik) wherein the corresponding R² and/or R³ is —C(═O)R⁶and/or —C(═O)R^(6A), respectively, among Compound (Ia) to Compound (Ih)obtained by the aforementioned the Preparing methods 1 to 7.

For example, Compound (Ij) can be obtained by treatment of Compound (Ik)in a solvent such as toluene and tetrahydrofuran, with an appropriatethiocarbonylating agent such as2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphophethane-2,4-disulfide(Lawesson's reagent), phosphorus pentasulfide and the like, at atemperature between room temperature and the boiling point of thesolvent for 1 to 24 hours. The thiocarbonylating agent is preferablyused in an amount of 2 to 10 equivalents to Compound (Ik).

Preparing Method 10

Among Compound (I), Compound (Im) wherein R³ is —C(═O)R^(6A) and R¹ andR^(2f) are combined to form a substituted or unsubstituted heterocyclicgroup together with the adjacent nitrogen atom can be obtained by thefollowing step from Compound (In) wherein R¹ and R^(2a) are hydrogenatoms among Compound (Ia) prepared by the Preparing method 1, or fromCompound (In) wherein R¹ is a hydrogen atom among Compound (Ic) preparedby the Preparing method 3:

(wherein R⁴, R⁵ and R^(6A) have the same meanings as those mentionedabove, respectively, X⁵ has the same meaning as that of theaforementioned X, R^(1b) and R^(2b) represent a substituted orunsubstituted heterocyclic group formed together with the adjacentnitrogen atom, said heterocyclic group formed together with the adjacentnitrogen atom has the same meaning as that of the aforementionedheterocyclic group (vii) formed together with the adjacent nitrogenatom, and the substituent in said substituted heterocyclic group formedtogether with the adjacent nitrogen atom has the same meaning as that ofthe aforementioned substituent (xiii) in the heterocyclic group.)

Compound (Ip) can be obtained from Compound (In) by the methodsdescribed in for example, Chem. Commun., Vol. 8, p. 873 (1998) and thelike, or the methods similar to the aforementioned methods.

Compound (Im) can be obtained by allowing Compound (Ip) to react withCompound (IX) in an inert solvent, for example, dichloromethane and thelike, at a temperature between 0° C. and 60° C. for 10 minutes to 24hours. Compound (IX) is preferably used in an amount of 2 to 50equivalents to Compound (Ip).

Alternatively, Compound (Im) can also be obtained from Compound (Ie-c)wherein R¹ is a hydrogen atom and R⁶ is an alkyl group substituted withcarboxyl group among Compound (Ie) prepared by the Preparing method 4 bythe method described in for example, Synthesis-Stuttgart, Vol. 5, p. 420(1991) or the methods similar to the aforementioned method.

Moreover, Compound (Im) can also be obtained from Compound (Ie-d)wherein R¹ is a hydrogen atom and R⁶ is an alkyl group substituted withhalogen among Compound (Ie) by the method described in for example,Shin-Jikken-Kagaku-Koza (New Experiment Chemistry Lecture) Vol. 14, p.1174 (Maruzen, 1978) and the like, or the methods similar to theaforementioned methods.

Furthermore, among Compound (I), Compound (Ij-a) wherein R³ is—C(═S)R^(6A) and R¹ and R² are combined to form a substituted orunsubstituted heterocyclic group together with the adjacent nitrogenatom can be obtained from Compound (Im) in the similar manner as theaforementioned the Preparing method 9.

In Compound (I), conversion of the functional group contained in R¹, R²,R³, R⁴ or R⁵ can also be carried out by the aforementioned steps, oralso by the other known methods (e.g., Comprehensive OrganicTransformations, R. C. Larock (1989) and the like].

Compound (I) having the desired functional group at the desired positioncan be obtained by carrying out the aforementioned methods inappropriate combination.

The intermediates and the objective compounds in the aforementionedpreparation methods can be purified and isolated by conducting apurification method ordinarily used in the synthetic organic chemistrysuch as filtration, extraction, washing, drying, concentration,recrystallization, various chromatography such as high performanceliquid chromatography, thin layer chromatography, silica gelchromatography and the like. The intermediates can also be subjected tothe next reaction without particular purification.

Some compounds among Compounds (I) may exist as position isomers,geometrical isomers, optical isomers, tautomers and the like. Allpossible isomers including the aforementioned isomers and mixturesthereof can be used for the antitumor agent of the present invention.

To obtain a salt of Compound (I), when Compound (I) obtained as a saltform, it may be purified as it is. When Compound (I) obtained as a freeform, it may be dissolved or suspended in an appropriate solvent, andadded with an appropriate acid or base to form a salt and then beisolated.

In addition, Compound (I) or a pharmacologically acceptable salt thereofmay exist in the form of adducts with water or variety of solvents,which also can be used for the antitumor agent of the present invention.

Specific examples of Compound (IA) obtained by the present invention areshown in Tables 1 to 10. However, the compounds of the present inventionare not limited to these examples.

The compounds shown in Tables 1 to 10 are used for the antitumor agentof the present invention, and other than the compounds, specificexamples of compounds used in the present invention are shown in Tables11 to 13. However, the compound used in the present invention is notlimited to these examples.

TABLE 1 (IA-i)

Ex- Com- ample pound No. No. R^(1A) R^(2A) R^(4A) 2 2 —H —COCH₃ —CH₂CH₃4 4 —H —COCH₃ —CH(CH₃)₂ 5 5 —H —COCH₃

7 7 —CH₃ —COCH₃ —CH₃ 8 8 —CH₂CH₃ —CH₂CH₃ —CH₃ 8 9 —CH₂CH₃ —COCH₃ —CH₃ 910 —(CH₂)₂CH₃ —(CH₂)₂CH₃ —CH₃ 9 11 —(CH₂)₂CH₃ —COCH₃ —CH₃ 129 136 —H—CO₂C(CH₃)₃ —CH₃ 130 137 —H —CON(CH₃)₂ —CH₃ 131 138

—CH₃ 132 139

—CH₃ 133 140 —H —CO(CH₂)₄CH₃ —CH₂NHSO₂CH₃ 134 141 —H —COCH═CHCH₃—CH₂NHSO₂CH₃ 135 142 —H

—CH₂NHSO₂CH₃ 136 143 —H —COC(CH₃)₂OCOCH₃ —CH₂NHSO₂CH₃ 137 144 —H—COC(CH₃)₂OH —CH₂NHSO₂CH₃ 138 145 —H —COCH₂OCH₃ —CH₂NHSO₂CH₃ 139 146 —H—COCH₂Cl —CH₂NHSO₂CH₃ 140 147 —H —COCH₂N(CH₃)₂ —CH₂NHSO₂CH₃ 141 148 —H—CO(CH₂)₃CO₂CH₃ —CH₂NHSO₂CH₃ 142 149 —H —CO(CH₂)₃CO₂H —CH₂NHSO₂CH₃ 143150

—CH₂NHSO₂CH₃ 144 151 —H —CO(CH₂)₃Br —CH₂NHSO₂CH₃ 145 152

—CH₂NHSO₂CH₃ 146 153 —H —CO(CH₂)₄Br —CH₂NHSO₂CH₃ 147 154

—CH₂NHSO₂CH₃ 148 155 —H —CO(CH₂)₅Br —CH₂NHSO₂CH₃ 149 156

—CH₂NHSO₂CH₃

TABLE 2 (IA-ii)

Ex- am- Com- ple pound No. No. R^(1A) R^(2A) R^(3A) 10 12 —CH₂Ph —CH₂Ph—COCH₃ 10 13 —CH₂Ph —COCH₃ —COCH₃ 12 15 —CH₃ —H —COCH₃ 13 16 —CH₃ —CH₃—COCH₃ 14 17 —CH₃ —H —COCH₂CH₃ 15 18 —CH₃ —COCH₃ —COCH₂CH₃ 16 19 —CH₃—COCH₂CH₃ —COCH₂CH₃ 17 20 —CH₃ —CO(CH₂)₂CH₃ —CO(CH₂)₂CH₃ 18 21 —CH₃—COCH(CH₃)₂ —COCH(CH₃)₂ 76 79 —CH₂CH═CH₂ —COCH₃ —COCH₃ 77 80 —CH₂CH═CH₂—H —COCH(CH₃)₂ 77 81 —CH₂CH═CH₂ —COCH₃ —COCH(CH₃)₂ 78 82 —H —COC(CH₃)₃—COC(CH₃)₃ 79 83 —CH₃ —H —COCH(CH₃)₂ 79 84 —CH₃ —COCH₃ —COCH(CH₃)₂ 80 85—H —COCH(CH₃)₂ —COCH(CH₃)₂ 81 86 —H —H —COCH(CH₃)₂ 81 87 —H —COCH₃—COCH(CH₃)₂ 82 88 —H —COCH(CH₃)₂ —COCH₃ 83 89 —H

—COCH₃ 84 90 —H —H —COCH₂CH(CH₃)₂ 84 91 —H —COCH(CH₃)₂ —COCH₂CH(CH₃)₂ 8592 —H —COCH₃ —COC(CH₃)₃ 86 93 —H —COC(CH₃)₃ —COCH₃ *Ph: phenyl

TABLE 3 (IA-iii)

Example Compound No. No. R^(1A) R^(4A) R^(5A) 22 25 —H —CH₃ —CH═CHPh 2326 —H —(CH₂)₃CH₃ —(CH₂)₃CH₃ 24 27 —H

25 28 —H

26 29 —H

28 31 —H

29 32 —H —CH₃

30 33 —H —CH₃

31 34 —H —CH₃

32 35 —H —CH₃

33 36 —H —CH₃

34 37 —H —CH₃

35 38 —H —CH₃

38 41 —CH₂CH₃ —CH₃

39 42 —H —CH₃

40 43 —H —CH₃

41 44 —H —CH₃

42 45 —H —CH₃

125 132 —H —CH₃

126 133 —H —CH₃

127 134 —H —CH₃

* Ph: phenyl

TABLE 4 (IA-iv)

Y^(1A) Example Compound (Substituting No. No. R^(1A) R^(4A) position) 4346 —H —CH₃ —CH₃ (2) 44 47 —H —CH₃ —CH₃ (3) 45 48 —H —CH₃ —CH₃ (4) 46 49—H —CH₂CH₃ —CH₂CH₃ (2) 47 50 —H —CH₃ —OCH₃ (2) 48 51 —H —CH₃ —OCH₃ (3)50 53 —H —CH₃ —F (2) 51 54 —H —CH₃ —F (3) 52 55 —H —CH₃ —F (4) 53 56 —H—CH₃ —Cl (2) 54 57 —CH₂CH₃ —CH₃ —Cl (2) 55 58 —H —CH₃ —Cl (3) 56 59 —H—CH₃ —Cl (4) 57 60 —H —CH₃ —Br (2) 58 61 —H —CH₃ —OCOCH₃ (2) 60 63 —H —H—OCOCH₃ (3) 61 64 —H —CH₃ —OCOCH₃ (4) 62 65 —H —CH₃ —NO₂ (2) 65 68 —H—CH₃ —OH (2) 66 69 —H —CH₃ —OH (3) 67 70 —H —CH₃ —OH (4) 68 71 —H —CH₃—CN (3) 69 72 —H —CH₃ —CN (4) 70 73 —H —CH₃ —CF₃ (3) 71 74 —H —CH₃ —COOH(2) 118 125 —CH₂CH₃ —CH₃ —OCOCH₃ (3) 119 126 —CH₂CH₃ —CH₃ —OH (3) 120127 —H —CH₃ —OCONHCH₂CH₃ (3)

TABLE 5 (IA-v)

Y^(1A) Y^(2A) Example Compound (Substituting (Substituting No. No.position) position) 72 75 —OCH₃ (2) —OCH₃ (6) 73 76 —OH (3) —OH (5) 7477 —OH (3) —OH (4) 75 78 —CH₃ (2) —CH₃ (4)

TABLE 6 (IA-vi)

Example Compound No. No. R^(1A) R^(4A) R^(5A) 87 94 —H —CH₂CH₃ —Ph 88 95—H —CH₂NHSO₂CH₃ —Ph 89 96 —CH₃ —CH₂NHSO₂CH₃ —Ph 90 97 —H —CH₂NHSO₂CH₂CH₃—Ph 91 98 —H —CH₂OCH₃ —Ph 92 99 —H —(CH₂)₂NHSO₂CH₃ —Ph 94 101 —H—CH₂NHCOCF₃ —Ph 97 104 —H —(CH₂)₂N(CH₃)₂ —Ph 98 105 —H —(CH₂)₂COOCH₃ —Ph99 106 —H —(CH₂)₂COOH —Ph 100 107 —H —(CH₂)₂CONH₂ —Ph 101 108 —H—(CH₂)₂CONHOH —Ph 102 109 —H —(CH₂)₂CONHCH₃ —Ph 103 110 —H—(CH₂)₂CON(CH₃)₂ —Ph 104 111 —H —(CH₂)₂CONH(CH₂)₂OH —Ph 105 112 —H—(CH₂)₂CONH(CH₂)₃CH₃ —Ph 106 113 —H

—Ph 107 114 —H —(CH₂)₃COOCH₃ —Ph 108 115 —H —(CH₂)₃COOH —Ph 109 116 —H—(CH₂)₃CONHCH₃ —Ph 110 117 —H —(CH₂)₃CONH₂ —Ph 123 130 —H —CH₃

128 135 —H —CH₃

154 161 —H

—Ph 155 162 —H

—Ph 156 163 —H

—Ph 156 164 —H

—Ph 157 165 —H

—Ph 158 166 —H —(CH₂)₃OH —Ph 159 167 —H —(CH₂)₃OSO₂NH₂ —Ph * Ph:phenyl * Ph: phenyl, Compound 164: an isomer of Compound 163

TABLE 7 (IA-vii)

Example Compound No. No. R^(1A) R^(4A) R^(5A) 93 100 —H —(CH₂)₂NHSO₂CH₃—Ph 95 102 —COCH(CH₃)₂ —CH₂NHSO₂CH₃ —Ph 96 103 —H —CH₂NHSO₂CH₃ —Ph 121128 —H —CH₃

122 129 —H —CH₃

124 131 —H —CH₃

* Ph: phenyl

TABLE 8 (IA-viii)

Example Compound No. No. R^(2A) R^(3A) R^(4A) 111 118 —H —COCH₃—CH₂NHSO₂CH₃ 112 119 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂CH₃ 113 120 —H—COC(CH₃)₃ —CH₂NHSO₂CH₃ 114 121 —CO(CH₂)₅Br —COC(CH₃)₃ —CH₂NHSO₂CH₃ 115122 —CO(CH₂)₅N₃ —COC(CH₃)₃ —CH₂NHSO₂CH₃ 116 123 —CO(CH₂)₅NH₂ —COC(CH₃)₃—CH₂NHSO₂CH₃ 117 124 —CO(CH₂)₅NHCOCH₃ —COC(CH₃)₃ —CH₂NHSO₂CH₃ 150 157 —H—COC(CH₃)₃ —(CH₂)₂NHSO₂CH₃ 151 158 —CO(CH₂)₃Br —COC(CH₃)₃—(CH₂)₂NHSO₂CH₃ 153 160 —COC(CH₃)₃ —CSCH₃ —CH₂NHSO₂CH₃ 160 168—COC(CH₃)₃ —COCH₃ —CH₂NHSO₂CH₂Cl 160 169 —COCH₃ —COCH₃ —CH₂NHSO₂CH₂Cl161 170 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂CH═CH₂ 161 171 —COC(CH₃)₃ —COC(CH₃)₃—CH₂NHSO₂CH═CH₂ 162 172 —COC(CH₃)₃ —COCH₃

163 173 —COC(CH₃)₃ —COCH₃ —CH₂NHSO₂(CH₂)₂NHCH₂CH₃ 164 174 —COC(CH₃)₃—COCH₃ —CH₂NHSO₂(CH₂)₂N(CH₃)₂ 165 175 —COC(CH₃)₃ —COCH₃—CH₂NHSO₂(CH₂)₂NH(CH₂)₂OH 166 176 —COC(CH₃)₃ —COC(CH₃)₃—CH₂NHSO₂(CH₂)₂NHCH₂CH₃ 167 177 —COC(CH₃)₃ —COC(CH₃)₃—CH₂NHSO₂(CH₂)₂N(CH₃)₂ 168 178 —H —COCH₃ —(CH₂)₂CO₂CH₃ 169 179—COC(CH₃)₃ —COCH₃ —(CH₂)₂CO₂CH₃ 170 180 —H —COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃171 181 —COC(CH₃)₃ —COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 174 184

—COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 175 185 —COCH₂CH₃ —COCH₂CH₃ —(CH₂)₂NHSO₂CH₃176 186 —H —COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 177 187 —COC(CH₃)₃ —COCH₂CH₃—(CH₂)₂NHSO₂CH₃ 180 190 —H —COC(CH₃)₃ —(CH₂)₂COOCH₃ 181 191

—COC(CH₃)₃ —(CH₂)₂COOCH₃

TABLE 9 (IA-xii)

Example Compound No. No. R^(1A) R^(2A) R^(3A) R^(4A) 152 159

—COC(CH₃)₃ —(CH₂)₂NHSO₂CH₃ 172 182

—COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 173 183

—COCH(CH₃)₂ —(CH₂)₂NHSO₂CH₃ 178 188

—COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 179 189

—COCH₂CH₃ —(CH₂)₂NHSO₂CH₃ 182 192

—COC(CH₃)₃ —(CH₂)₂COOCH₃ 183 193

—COC(CH₃)₃ —(CH₂)₂COOH 184 194

—COC(CH₃)₃ —(CH₂)₂CONH(CH₂)₂OH

TABLE 10 (IA-xiii)

Example Compound No. No. R^(2A) R²⁸ Y^(3A) 185 195 —COC(CH₃)₃ —OCOCH₃ —H186 196 —COC(CH₃)₃ —OH —H 187 197 —H —H —OCOCH₃ 188 198 —COC(CH₃)₃ —H—OCOCH₃ 189 199 —COC(CH₃)₃ —H —OH

TABLE 11 (I-ix)

Example Compound No. No. R² R⁴ 1 1 —COCH₃ —CH₃ 3 3 —COCH₃ —(CH₂)₃CH₃ 6 6—COCH₃ —Ph 11 14 —H —CH₃ * Ph: phenyl

TABLE 12 (I-x)

Example Compound No. No. R¹ R⁴ R⁵ 19 22 —H —CH₃ —CH₃ 20 23 —H —CH₃—(CH₂)₃CH₃ 21 24 —H —CH₃ —(CH₂)₂Ph 27 30 —H

36 39 —H —CH₃

37 40 —H —CH₃

* Ph: phenyl

TABLE 13 (I-xi)

Y¹ Example Compound (Substituting No. No. R¹ R⁴ position) 49 52 —H —CH₃—OCH₃ (4) 59 62 —H —CH₃ —OCOCH₃ (3) 63 66 —H —CH₃ —NO₂ (3) 64 67 —H —CH₃—NO₂ (4)

Next, the pharmacological activity of typical Compounds (I) will beexplained by the following test example.

Test Example 1 Antiproliferative Activity in HCT 116 Human Colon CancerCells

HCT 116 cells (ATCC No.: CCL-247) were placed on a 96-well microliterplate (Nunc, 167008) at a density of 1×10³ cells/well. The plate wasincubated in a 5% CO₂ incubator at 37° C. for 24 hours, and then to theplate was added test compounds diluted stepwise to 100 mL/well in total,and the plate was further incubated in a 5% CO₂ incubator at 37° C. for72 hours. To the culture medium, the XTT (sodium3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium)-bis(4-methoxy-6-nitro)benzenesulfonicacid hydrate) labeling mixture (Roche Diagnostics, 1465015) wasdispensed in 50 mL/well portions, then the plate was incubated in a 5%CO₂ incubator at 37° C. for 1 hour, and the absorbance was measured at490 nm and 655 nm with a microplate spectrophotometer (Bio-Rad, Model550). The inhibitory activity against cell proliferation was shown as aconcentration of 50% proliferation inhibition, GI₅₀.

GI₅₀ calculation method: The value (difference in absorbance) wascalculated by subtracting the absorbance at 655 nm from the absorbanceat 490 nm of each well. The difference in absorbance obtained from thecells untreated with a test compound was defined as 100%, and comparedwith the difference in absorbance obtained from the cells treated withthe solution of the compound in the known concentration, and thereby theconcentration of the compound of 50% inhibition against cellproliferation was calculated to obtain GI₅₀.

The results of the typical compounds obtained in Test example 1 areshown in Table 14. Compounds 138, 152, 165, 170, 173, and 199 showed theGI₅₀ value less than 10 μmol/L.

TABLE 14 Compound No. GI₅₀ (μmol/L) 1 1.0 7 0.48 18 0.62 41 0.60 46 0.5757 0.53 69 0.23 82 0.18 99 0.063 104 0.074 107 0.061 134 0.40

Compound (I) or Compound (IA), or a pharmacologically acceptable saltthereof, per se, can be administered, however, is generally desired tobe provided as a form of various pharmaceutical preparations. Also, thepharmaceutical preparations are used for animals or human.

The pharmaceutical preparations according to the present invention cancomprise as an active ingredient Compound (I) or Compound (IA), or apharmacologically acceptable salt thereof, solely or as a mixture withany other effective ingredient for the treatment. The pharmaceuticalpreparations are manufactured by mixing the active ingredient with oneor more of pharmacologically acceptable carriers using any method wellknown in the technical field of pharmaceutical science.

As for administration routes, it is preferred to chose the mosteffective route for the treatment such as oral administration orparenteral administration, for example, intravenous administration andthe like.

Examples of formulations for administration include tablets, injectionsand the like.

Examples of the pharmaceutical carrier used include lactose, mannitol,glucose, hydroxypropyl cellulose, starch, magnesium stearate, sorbitanfatty acid ester, glyceric acid ester, polyvinyl alcohol, distilledwater for injection, physiological saline, propylene glycol,polyethylene glycol, ethanol and the like. The pharmaceuticalpreparation according to the present invention may comprise othervarious additives such as excipients, lubricants, binders,disintegrator, isotonicities and emulsifiers.

Compound (I) or Compound (IA), or a pharmacologically acceptable saltthereof is generally administered systemically or locally in the form ofan oral or parenteral preparation when used for the aforementionedpurpose. The dose and the frequency of administration may vary dependingon the administration form, the age and body weight of a patient, natureand severity of the condition to be treated, and the like. Generally,0.1 to 1,000 mg/kg, preferably 0.5 to 500 mg/kg per singleadministration for an adult may be administered orally or parenterally,once a day or a few times a day, or may be continuously administeredintravenously for 1 to 24 hours a day. However, the dose and thefrequency of administration may vary depending on the aforementionedvarious conditions and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in detail with reference to thefollowing examples.

The spectra of proton nuclear magnetic resonance (¹H NMR) used inExamples were measured at 270 or 300 MHz, and exchangeable hydrogen maynot always be clearly observed depending on the compound and themeasurement conditions. For the descriptions of the multiplicity ofsignals, those generally applied are used, and the symbol “br”represents an apparent broad signal.

Example 1 (Compound 1)

Step 1: Acetophenone (4.00 g, 33.3 mmol) and thiosemicarbazide (3.15 g,34.6 mmol) were dissolved in methanol (30 mL). To the solution was addedhydrochloric acid (0.1 mL) and the mixture was vigorously stirred atroom temperature for 15 hours. To the reaction mixture was added water(30 mL), and the deposited crystals were collected by filtration. Thecollected crystals were washed with water and diisopropyl ether, andthen dried to obtain acetophenone=thiosemicarbazone (5.64 g, 88%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.30 (s, 3H), 7.37-7.40 (m, 3H),7.91-7.94 (m, 3H), 8.27 (br s, 1H), 10.21 (br s, 1H).

Step 2: Acetophenone=thiosemicarbazone (300 mg, 0.889 mmol) obtainedabove was dissolved in acetic anhydride (1.0 mL, 11 mmol). After beingrefluxing under heating, the solution was cooled to room temperaturewith vigorous stirring. To the reaction mixture was added diisopropylether (3 mL), and the deposited crystals were collected by filtration.After the collected crystals were suspended in diisopropyl ether andstirred for 3 hours, the crystals were collected by filtration and driedto obtain Compound 1 (195 mg, 72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.19 (s, 3H), 2.28 (s,3H), 7.24-7.36 (br s, 5H), 11.63 (br s, 1H)

Example 2 (Compound 2)

Step 1: In a manner similar to that in Step 1 of Example 1,propiophenone=thiosemicarbazone (759 mg, 88%) was obtained frompropiophenone (541 mg, 3.92 mmol) and thiosemicarbazide (382 mg, 4.18mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.01 (t, J=7.4 Hz, 3H), 2.85 (br q,J=7.4 Hz, 2H), 7.39 (m, 3H), 7.89 (m, 3H), 8.24 (br s, 1H), 10.30 (br s,1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 2(601 mg, 76%) was obtained from propiophenone=thiosemicarbazone (559 mg,2.70 mmol) obtained above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.02 (t, J=7.1 Hz, 3H), 2.00 (s, 3H),2.21 (s, 3H), 2.38 (dt, J=7.1, 7.3 Hz, 1H), 2.85 (dt, J=7.1, 7.3 Hz,1H), 7.23-7.38 (m, 5H), 11.59 (br s, 1H)

Example 3 (Compound 3)

Step 1: In a manner similar to that in Step 1 of Example 1,n-butyl(phenyl)methanone=thiosemicarbazone (589 mg, 63%) was obtainedfrom n-butyl(phenyl)methanone (649 mg, 4.00 mmol) and thiosemicarbazide(367 mg, 4.03 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.99 (t, J=7.3 Hz, 3H), 1.38-1.49 (m,4H), 2.96-2.99 (m, 2H), 7.37-7.39 (m, 3H), 7.87-7.91 (m, 3H), 8.26 (brs, 1H), 10.36 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 3(168 mg, 62%) was obtained fromn-butyl(phenyl)methanone=thiosemicarbazone (200 mg, 0.850 mmol) obtainedabove.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.96 (t, J=7.3 Hz, 3H), 1.25-1.34 (m,1H), 1.36-1.54 (m, 2H), 1.68-1.80 (m, 1H), 2.18 (s, 3H), 2.20-2.26 (m,1H), 2.26 (s, 3H), 2.99-3.10 (m, 1H), 7.22-7.40 (m, 5H), 8.22 (br s, 1H)

Example 4 (Compound 4)

Step 1: In a manner similar to that in Step 1 of Example 1,isopropyl(phenyl)methanone=thiosemicarbazone (613 mg, 68%) was obtainedfrom isopropyl(phenyl)methanone (608 mg, 4.10 mmol) andthiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.07 (d, J=6.9 Hz, 6H), 2.82 (m, 1H),7.28 (br d, J=6.3 Hz, 2H), 7.51-7.60 (m, 3H), 7.78 (br s, 1H), 8.23 (brs, 1H), 8.43 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 4(217 mg, 52%) was obtained fromisopropyl(phenyl)methanone=thiosemicarbazone (300 mg, 1.36 mmol)obtained above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.04 (d, J=6.9 Hz, 3H), 1.13 (d, J=6.9Hz, 3H), 2.09 (s, 3H), 2.19 (s, 3H), 3.86 (m, 1H), 7.25-7.36 (m, 3H),7.75 (br d, J=7.3 Hz, 2H), 8.08 (br s, 1H)

Example 5 (Compound 5)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 5(130 mg, 10%) was obtained from cyclopropyl(phenyl)methanone (649 mg,4.00 mmol) and thiosemicarbazide (367 mg, 4.03 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.60-0.98 (m, 4H), 1.84 (s, 3H), 2.34(s, 3H), 2.45 (m, 1H), 7.20-7.35 (m, 3H), 7.54 (br d, J=8.7 Hz, 2H),9.40 (br s, 1H)

Example 6 (Compound 6)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 6(150 mg, 29%) was obtained from benzophenone (0.20 g, 2.19 mmol) andthiosemicarbazide (400 mg, 2.20 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.89 (s, 3H), 2.32 (s, 3H), 7.25-7.52(m, 10H), 9.13 (br s, 1H)

Example 7 (Compound 7)

Step 1: In a manner similar to that in Step 1 of Example 1,acetophenone=4-methylthiosemicarbazone (1.51 g, 77%) was obtained from4-methylthiosemicarbazide (1.00 g, 9.51 mmol) and acetophenone (1.33 mL,11.4 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 7(1.03 g, 47%) was obtained from acetophenone=4-methylthiosemicarbazone(1.00 g, 9.51 mmol) obtained above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.21 (s, 3H), 2.23 (s, 3H), 2.26 (s,3H), 3.41(s, 3H), 7.28-7.36 (m, 5H)

Example 8 (Compounds 8 and 9)

To a solution of 60% sodium hydride (110 mg, 2.70 mmol) inN,N-dimethylformamide (10.0 mL) was added Compound 1 (50.0 mg, 1.80mmol) prepared in Example 1, and the mixture was stirred at roomtemperature for 30 minutes. To the reaction mixture was added ethyliodide (0.22 mL, 2.70 mmol) and the reaction mixture was further stirredat room temperature for 12 hours. To the reaction mixture was added 5%aqueous ammonium chloride and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride and then dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/n-hexane=1/1) to obtainCompound 8 (120 mg, 22%) and Compound 9 (330 mg, 60%).

Compound 8

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.19 (t, J=7.0 Hz, 6H), 2.23 (s, 3H),2.41 (s, 3H), 3.26 (q, J=7.0 Hz, 4H), 7.21-7.45 (m, 5H)

Compound 9

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.36 (t, J=7.2 Hz , 3H), 2.24 (s, 6H),2.37 (s, 3H), 3.91 (q, J=7.2 Hz, 2H), 7.22-7.41 (m, 5H)

Example 9 (Compounds 10 and 11)

In a manner similar to that in Example 8, Compound 10 (0.15 g, 26%) andcompound 11 (0.27 g, 48%) were obtained from Compound 1 (0.50 g, 1.80mmol) prepared in Example 1 and n-propyl iodide (0.26 mL, 2.70 mmol).

Compound 10

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.89 (t, J=7.6 Hz, 6H), 1.61 (br q,J=7.6 Hz, 4H), 2.27 (s, 3H), 2.40 (s, 3H), 3.14 (br t, J=1.3 Hz, 4H),7.21-7.47 (m, 5H)

Compound 11

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.00 (t, J=7.3 Hz, 3H), 1.74-1.82 (m,2H), 2.28 (s, 6H), 2.36 (s, 3H), 3.75-3.86 (m, 2H), 7.21-7.44 (m, 5H)

Example 10 (Compounds 12 and 13)

In a manner similar to that in Example 8, Compound 12 (120 mg, 16%) andCompound 13 (0.22 g, 33%) were obtained from Compound 1 (500 mg, 1.80mmol) prepared in Example 1 and benzyl bromide (0.32 mL, 2.70 mmol).

Compound 12

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.24 (s, 3H), 2.46 (s, 3H), 4.43 (s,4H), 7.14-7.49 (m, 15H)

Compound 13

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.26 (s, 3H), 2.36 (s,3H), 5.11 (br s, 2H), 7.22-7.38 (m, 10H)

Example 11 (Compound 14)

To acetophenone=thiosemicarbazone (10.0 g, 51.8 mmol) prepared in Step 1of Example 1 was added acetic anhydride (4.90 mL, 51.9 mmol) andpyridine (8.40 mL, 104 mmol), and the mixture was stirred at roomtemperature for 12 hours. After the reaction mixture was concentratedunder reduced pressure, ethyl acetate and 2 mol/L aqueous sodiumhydroxide was added, and the mixture was subjected to separation. Theorganic layer was washed with saturated aqueous ammonium chloride andsaturated aqueous sodium chloride, and dried over anhydrous sodiumsulfate, and then the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/n-hexane=1/1) to obtain Compound 14 (9.22 g, 76%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.12 (s, 3H), 2.31 (s, 3H), 6.49 (brs, 2H), 7.21-7.41 (m, 5H)

Example 12 (Compound 15)

Compound 7 (550 mg, 1.89 mmol) prepared in Example 7 was dissolved inN,N-dimethylformamide (10.0 mL). To the solution was added 60% sodiumhydride (0.23 g, 5.75 mmol) and the mixture was stirred at roomtemperature for 30 minutes. To the reaction mixture was added water andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous ammonium chloride and then dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/n-hexane=1/1) to obtain Compound 15 (0.31 g, 66%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.17 (s, 3H), 2.41 (s, 3H), 2.91 (br d,J=5.0 Hz, 3H), 3.92 (br s, 1H), 7.25-7.47 (m, 5H)

Example 13 (Compound 16)

To a solution of 60% sodium hydride (50.0 mg, 1.20 mmol) inN,N-dimethylformamide (2.0 mL) was added Compound 14 (100 mg, 0.41 mmol)prepared in Example 11, and the mixture was stirred at room temperaturefor 30 minutes. To the reaction mixture was added methyl iodide (0.08mL, 1.24 mmol), and the mixture was further stirred at room temperaturefor 12 hours. To the reaction mixture was added 5% aqueous ammoniumchloride and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride and then driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=1/1) to obtain Compound 16 (70.0mg, 67%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.26 (s, 3H), 2.41 (s, 3H), 2.91 (s,6H), 7.23-7.48 (m, 5H)

Example 14 (Compound 17)

In a manner similar to that in Example 12, Compound 17 (580 mg, 71%) wasobtained from Compound 19 (1.00 g, 3.13 mmol) obtained in theafter-mentioned Example 16.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=7.2 Hz, 3H), 2.39 (s, 3H),2.61 (q, J=7.2 Hz, 2H), 2.88 (d, J=6.3 Hz, 3H), 4.02 (br d, J=6.3 Hz,1H), 7.22-7.38 (m, 5H)

Example 15 (Compound 18)

Compound 17 (100 mg, 0.38 mmol) prepared in Example 14 was dissolved inacetone (2.0 mL). To the solution was added acetyl chloride (0.15 mL,2.11 mmol) and pyridine (0.15 mL, 1.85 mmol), and the mixture wasstirred at room temperature for 2 hours. To the reaction mixture wasadded ethyl acetate and 2 mol/L aqueous sodium hydroxide, and thesolution was subjected to separation. The organic layer was washed withsaturated aqueous ammonium chloride and saturated aqueous sodiumchloride, and dried over anhydrous sodium sulfate, and then the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/n-hexane=1/2) to obtainCompound 18 (0.07 g, 59%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (t, J=7.6 Hz, 3H), 2.27 (s, 3H),2.35 (s, 3H), 2.65 (q, J=7.6 Hz, 2H), 3.45 (s, 3H), 7.23-7.42 (m, 5H)

Example 16 (Compound 19)

To acetophenone=4-methylthiosemicarbazone (2.00 g, 9.66 mmol) preparedin Step 1 of Example 7 was added propionic anhydride (8.67 mL, 67.6mmol), and the mixture was heated and stirred at 100° C. for 3 hours. Tothe reaction mixture was added ethyl acetate and 2 mol/L aqueous sodiumhydroxide. After the mixture was stirred at room temperature for 30minutes, the mixture was subjected to separation. The organic layer waswashed with saturated aqueous ammonium chloride and saturated aqueoussodium chloride, and dried over anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/n-hexane=1/2) toobtain Compound 19 (1.39 g, 45%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (t, J=7.3 Hz, 3H), 1.17 (t, J=7.5Hz, 3H), 2.36 (s, 3H), 2.54 (q, J=7.3 Hz, 2H), 2.66 (q, J=7.5 Hz, 2H),3.45 (s, 3H), 7.21-7.42 (m, 5H)

Example 17 (Compound 20)

In a manner similar to that in Example 16, Compound 20 (1.55 g, 46%) wasobtained from acetophenone=4-methylthiosemicarbazone (2.00 g, 9.66 mmol)prepared in Step 1 of Example 7 and butyric anhydride (11.1 mL, 67.8mmol).

¹H NMR (270 MHz, CDCl₃) d(ppm): 0.95 (t, J=7.3 Hz, 3H), 0.98 (t, J=7.4Hz, 3H), 1.15-1.78 (m, 4H), 2.35 (s, 3H), 2.49 (t, J=7.3 Hz, 2H), 2.61(t, J=7.4 Hz, 2H), 3.45 (s, 3H), 7.21-7.42 (m, 5H)

Example 18 (Compound 21)

In a manner similar to that in Example 16, Compound 21 (1.43 g, 43%) wasobtained from acetophenone=4-methylthiosemicarbazone (2.00 g, 9.66 mmol)prepared in Step 1 of Example 7 and isobutyric anhydride (11.2 mL, 67.5mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.05-1.25 (m, 12H), 2.34 (s, 3H), 2.99(q, J=7.3 Hz, 1H), 3.25 (q, J=7.5 Hz, 1H), 3.50 (s, 3H), 7.21-7.45 (m,5H)

Example 19 (Compound 22)

Step 1: In a manner similar to that in Step 1 of Example 1,acetone=thiosemicarbazone (215 mg, 41%) was obtained from acetone (4.8g, 40 mmol) and thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.89 (s, 3H), 1.91 (s, 3H), 7.51 (brs, 1H), 7.98 (br s, 1H), 9.90 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 22(151 mg, 61%) was obtained from acetone=thiosemicarbazone (150 mg, 1.14mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.98 (s, 6H), 2.19 (s, 3H), 2.20 (s,3H), 9.06 (br s, 1H)

Example 20 (Compound 23)

Step 1: In a manner similar to that in Step 1 of Example 1,2-hexanone=thiosemicarbazone (671 mg, 97%) was obtained from 2-hexanone(401 mg, 4.00 mmol) and thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.88 (t, J=6.9 Hz, 3H), 1.23-1.31 (m,2H), 1.41-1.50 (m, 2H), 1.88 (s, 3H), 2.17-2.23 (m, 2H), 7.44 (br s,1H), 8.02 (br s, 1H), 9.88 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 23(255 mg, 57%) was obtained from 2-heranone=thiosemicarbazone (300 mg,1.73 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.90 (t, J=6.9 Hz, 3H), 1.23-1.38 (m,3H), 1.52-1.56 (m, 1H), 1.84-2.18 (m, 1H), 1.97 (s, 3H), 2.18 (s, 3H),2.19 (s, 3H), 2.44-2.55 (m, 1H), 8.68 (br s, 1H)

Example 21 (Compound 24)

Step 1: In a manner similar to that in Step 1 of Example 1,benzylacetone=thiosemicarbazone (788 mg, 89%) was obtained frombenzylacetone (593 mg, 4.00 mmol) and thiosemicarbazide (367 mg, 4.03mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.92 (s, 3H), 2.52 (m, 2H), 2.84 (m,2H), 7.14-7.30 (m, 5H), 7.43 (br s, 1H), 8.03 (br s, 1H), 9.94 (br s,1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 24(382 mg, 92%) was obtained from benzylacetone=thiosemicarbazone (300 mg,1.36 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.00 (s, 3H), 2.17 (s, 3H), 2.13 (dd,J=2.3, 10.2 Hz, 1H), 2.19 (s, 3H), 2.59 (dd, J=2.2, 10.2 Hz, 1H), 2.87(br d, J=12.2 Hz, 1H), 2.95 (br s, J=11.8 Hz, 1H), 7.14-7.29 (m, 5H),8.39 (br s, 1H)

Example 22 (Compound 25)

Step 1: In a manner similar to that in Step 1 of Example 1,benzylideneacetone=thiosemicarbazone (730 mg, 80%) was obtained 1 frombenzylideneacetone (610 mg, 4.17 mmol) and thiosemicarbazide (371 mg,4.07 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.13 (s, 3H), 6.89 (d, J=16.8 Hz, 1H),7.10 (d, J=16.8 Hz, 1H), 7.27-7.41 (m, 3H), 7.43-7.56 (m, 2H), 7.78 (brs, 1H), 8.26 (br s, 1H), 10.27 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 25(195 mg, 72%) was obtained from benzylideneacetone=thiosemicarba.zone(300 mg, 0.889 mmol) prepared above.

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.13 (s, 3H), 2.15 (s, 3H), 2.23 (s,3H), 6.62 (d, J=12.2 Hz, 1H), 6.65 (d, J=12.2 Hz, 1H), 7.20-7.39 (m,5H), 8.57 (br s, 1H)

Example 23 (Compound 26)

Step 1: In a manner similar to that in Step 1 of Example 1,5-Nonanone=thiosemicarbazone (553 mg, 64%) was obtained from 5-nonanone(569 mg, 4.00 mmol) and thiosemicarbazide (364 mg, 3.99 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.87 (t, J=6.9 Hz, 6H), 1.20-1.53 (m,8H), 2.17-2.22 (m, 2H), 2.31-2.37 (m, 2H), 7.40 (br s, 1H), 8.00 (br s,1H), 10.03 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 26(245 mg, 59%) was obtained from 5-nonanone=thiosemicarbazone (300 mg,1.39 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.90 (t, J=6.9 Hz, 6H), 1.18-1.37 (m,6H), 1.55-1.63 (m, 2H), 1.77-1.88 (m, 2H), 2.18 (s, 3H), 2.19 (s, 3H),2.45-2.56 (m, 2H), 8.90 (br s, 1H)

Example 24 (Compound 27)

Step 1: In a manner similar to that in Step 1 of Example 1,a-tetralone=thiosemicarbazone (797 mg, 88%) was obtained froma-tetralone (604 mg, 4.13 mmol) and thiosemicarbazide (368 mg, 4.04mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.78-1.82 (m, 2H), 2.65-2.75 (m, 4H),7.15-7.27 (m, 3H), 7.97 (br s, 1H), 8.20-8.40 (m, 2H), 10.10 (br a, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 27(324 mg, 78%) was obtained from a-tetralone=thiosemicarbazone (300 mg,1.37 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.89 (s, 3H), 2.09-2.22 (m, 2H), 2.28(s, 3H), 2.36-2.41 (m, 1H), 2.80-2.86 (m, 2H), 2.97-3.08 (m, 1H), 7.01(br d, J=8.6 Hz, 1H), 7.08-7.18 (m, 2H), 7.40 (br d, J=7.3 Hz, 1H), 9.24(br s, 1H)

Example 25 (Compound 28)

Step 1: In a manner similar to that in Step 1 of Example 1,β-tetralone=thiosemicarbazone (684 mg, 75%) was obtained from8-tetralone (607 mg, 4.15 mmol) and thiosemicarbazide (379 mg, 4.16mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 28(301 mg, 65%) was obtained from β-tetralone=thiosemicarbazone (334 mg,1.53 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.12 (s, 3H), 2.15-2.30 (m, 1H), 2.24(s, 3H), 3.05-3.09 (m, 2H), 3.14 (br d, J=15.8 Hz, 1H), 3.23-3.41 (m,1H), 4.38 (br d, J=15.8 Hz, 1H), 6.99-7.00 (m, 1H), 7.02-7.25 (m, 3H),8.42 (br s, 1H)

Example 26 (Compound 29)

Step 1: In a manner similar to that in Step 1 of Example 1,1-indanone=thiosemicarbazone (1.54 g, 94%) was obtained from 1-indanone(1.06 g, 8.00 mmol) and thiosemicarbazide (740 mg, 8.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.85-2.89 (m, 2H), 3.03-3.08 (n, 2H),7.28-7.38 (m, 3H), 7.87 (br d, J=7.6 Hz, 1H), 7.92 (br s, 1H), 8.17 (brs, 1H), 10.2 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 29(184 mg, 44%) was obtained from 1-indanone=thiosemicarbazone (300 mg,1.46 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.17 (s, 3H), 2.24 (s, 3H), 2.58-2.65(m, 1H), 2.96-3.07 (m, 1H), 3.13-3.21 (m, 2H), 7.15-7.27 (m, 3H),7.32-7.37 (m, 1H), 9.60 (br s, 1H)

Example 27 (Compound 30)

Step 1: In a manner similar to that in Step 1 of Example 1,cyclohexanone=thiosemicarbazone (479 mg, 70%) was obtained fromcyclohexanone (393 mg, 4.00 mmol) and thiosemicarbazide (364 mg, 3.99mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.55 (br s, 6H), 2.19-2.23 (m, 2H),2.38 (br s, 2H), 7.50 (br s, 1H), 7.93 (br s, 1H), 10.13 (br s, 1H)

Step 2: In a manner'similar to that in Step 2 of Example 1, Compound 30(214 mg, 72%) was obtained from cyclohexanone=thiosemicarbazone (200 mg,1.17 mmol) prepared above.

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.25-1.53 (n, 3H), 1.58-1.68 (m, 1H),1.81-1.86 (m, 2H), 2.03-2.08 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H),2.90-3.01 (m, 2H), 7.95 (br s, 1H)

Example 28 (Compound 31)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 31(214 mg, 20%) was obtained from 2-norbornanone (452 mg, 4.10 mmol) andthiosemicarbazide (377 mg, 4.14 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32-1.67 (m, 5H), 1.76-1.89 (m, 2H),2.18 (s, 3H), 2.19 (br s, 1H), 2.21 (s, 3H), 2.26 (br s, 1H), 3.60 (brd, J=13.9 Hz, 1H), 8.20 (br s, 1H)

Example 29 (Compound 32)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 32(214 mg, 32%) was obtained from 1′-acetonaphthone (344 mg, 2.02 mmol)and thiosemicarbazide (190 mg, 2.08 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.06 (s, 3H), 2.07 (s, 3H), 2.33 (s,3H), 7.45-7.65 (m, 4H), 7.89-7.99 (m, 3H), 11.50 (br s, 1H).

Example 30 (Compound 33)

Step 1: In a manner similar to that in Step 1 of Example 1,2′-acetonaphthone=thiosemicarbazone (448 mg, 92%) was obtained from2′-acetonaphthone (342 mg, 2.10 mmol) and thiosemicarbazide (189 mg,2.07 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (s, 3H), 7.53 (m, 2H), 7.86-8.05(m, 4H), 8.28-8.34 (m, 3H), 10.28 (br a, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 33(302 mg, 90%) was obtained from 2′-acetonaphthone=thiosemicarbazone (250mg, 1.03 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.02 (s, 3H), 2.22 (s, 3H), 2.38 (s,3H), 7.51-7.55 (m, 3H), 7.85-7.95 (m, 4H), 11.68 (br s, 1H)

Example 31 (Compound 34)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(2-pyridyl)ethanone=thiosemicarbazone (694 mg, 88%) was obtained from2-acetylpyridine (485 mg, 4.00 mmol) and thiosemicarbazide (369 mg, 4.05mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.38 (s, 3H), 7.37 (br t, J=6.3 Hz,1H), 7.78 (br t, J=7.2 Hz, 1H), 8.13 (br s, 1H), 8.40 (br s, 1H), 8.41(br d, J=8.2 Hz, 1H), 8.56 (br d, J=6.6 Hz, 1H), 10.31 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 34(160 mg, 37%) was obtained from 1-(2-pyridypethanone=thiosemicarbazorte(304 mg, 1.56 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.09 (s, 3H), 2.26 (s, 3H), 2.42 (s,3H), 7.17 (br t, J=6.9 Hz, 1H), 7.38 (br d, J=8.2 Hz, 1H), 7.68 (br t,J=7.7 Hz, 1H), 8.44 (br s, 1H), 8.58 (br d, J=6.3 Hz, 1H)

Example 32 (Compound 35)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(3-pyridyl)ethanone=thiosemicarbazone (722 mg, 93%) was obtained from3-acetylpyridine (484 mg, 4.00 mmol) and thiosemicarbazide (388 mg, 4.00mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.32 (s, 3H), 7.32-7.42 (m, 1H), 8.07(br s, 1H), 8.29-8.34 (m, 2H), 8.54-8.57 (m, 1H), 9.09 (br s, 1H), 10.32(br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 35(213 mg, 72%) was obtained from 1-(3-pyridypethanone=thiosemicarbazone(205 mg, 1.05 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.14 (s, 3H), 2.21 (s, 3H), 2.39 (s,3H), 7.31 (br dd, J=5.4, 7.9 Hz, 1H), 7.75 (br d, J=7.9 Hz, 1H), 8.52(br d, J=5.4 Hz, 1H), 8.72 (br s, 1H), 9.08 (br s, 1H)

Example 33 (Compound 36)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(4-pyridyl)ethanone=thiosemicarbazone (722 mg, 95%) was obtained from4-acetylpyridine (507 mg, 4.19 mmol) and thiosemicarbazide (408 mg, 4.46mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 36(389 mg, 85%) was obtained from 1-(4-pyridyl)ethanone=thiosemicarbazone(318 mg, 1.64 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.25 (s, 3H), 2.35 (s,3H), 7.30 (d, J=6.3 Hz, 2H), 8.46 (br s, 1H), 8.60 (d, J=6.3 Hz, 2H)

Example 34 (Compound 37)

Step 1: In a manner similar to that in Step 1 of Example 1,1-pyrazinylethanone=thiosemicarbazone (714 mg, 92%) was obtained fromacetylpyrazine (489 mg, 4.00 mmol) and thiosemicarbazide (366 mg, 4.00mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 37(489 mg, 85%) was obtained from 1-pyrazinylethanone=thiosemicarbazone(400 mg, 2.05 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.26 (s, 3H), 2.42 (s,3H), 8.06 (br s, 1H), 8.46 (d, J=2.7 Hz, 1H), 8.52 (dd, J=1.7, 2.7 Hz,1H), 8.71 (d, J=1.7 Hz, 1H)

Example 35 (Compound 38)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(2-pyrrolyl)ethanone=thiosemicarbazone (408 mg, 55%) was obtained from2-acetylpyrrole (437 mg, 4.00 mmol) and thiosemicarbazide (374 mg, 4.09mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 38(504 mg, 95%) was obtained from 1-(2-pyrrolyl)ethanone=thiosemicarbazone(314 mg, 1.72 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.12 (s, 3H), 2.21 (s, 3H), 2.38 (s,3H), 2.55 (s, 3H), 6.17-6.22(m, 2H), 7.11 (br s, 1H), 8.13 (br s, 1H)

Example 36 (Compound 39)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(2-furyl)ethanone=thiosemicarbazone (441 mg, 60%) was obtained from2-acetylfuran (444 mg, 4.00 mmol) and thiosemicarbazide (368 mg, 4.03mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 39(217 mg, 83%) was obtained from 1-(2-furyl)ethanone=thiosemicarbazone(180 mg, 0.982 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.13 (s, 3H), 2.22 (s, 3H), 2.30 (s,3H), 6.31 (m, 2H), 7.36 (br s, 1H), 8.43 (br s, 1H)

Example 37 (Compound 40)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(2-thienyl)ethanone=thiosemicarbazone (636 mg, 78%) was obtained from2-acetylthiophene (521 mg, 4.13 mmol) and thiosemicarbazide (376 mg,4.11 mmol).

Step 2: In a manner similar to that in Step 2 of. Example 1, Compound 40(549 mg, 78%) was obtained from 1-(2-thienyl)ethanone=thiosemicarbazone(498 mg, 2.50 mmol) prepared above.

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.07 (s, 3H), 2.24 (s, 3H), 2.42 (s,3H), 6.89 (br t, J=7.2 Hz, 1H), 7.06 (dd, J=6.9, 7.2 Hz 1H), 7.24 (br d,J=6.9 Hz, 1H), 8.81 (br s, 1H)

Example 38 (Compound 41)

In a manner similar to that in Example 8, Compound 41 (148 mg, 52%) wasobtained in from Compound 40 (260 mg, 0.918 mmol) prepared in Example37.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.36 (t, J=7.0 Hz, 3H), 2.25 (s, 3H),2.30 (s, 3H), 2.43 (s, 3H), 3.92 (br q, J=7.0 Hz, 2H), 6.91 (br t, J=5.2Hz, 1H), 7.06 (br d, J=5.2 Hz, 1H), 7.24 (br d, J=5.2 Hz, 1H)

Example 39 (Compound 42)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(3-methyl-2-thienyl)ethanone=thiosemicarbazone (410 mg, 48%) wasobtained from 2-acetyl-3-methylthiophene (561 mg, 4.00 mmol) andthiosemicarbazide (374 mg, 4.09 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 42(335 mg, 93%) was obtained from1-(3-methyl-2-thienyDethanone=thiosemicarbazone (260 mg, 1.22 mmol)prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.02 (s, 3H), 2.19 (s, 3H), 2.24 (s,3H), 2.38 (s, 3H), 6.78 (d, J=5.0 Hz, 1H), 7.07 (d, J=5.0 Hz, 1H), 9.37(br s, 1H)

Example 40 (Compound 43)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(benzo[b]thiophen-2-yl)ethanone=thiosemicarbazone (990 mg, 99%) wasobtained from 1-(benzo[b]thiophen-2-yl)ethanone (705 mg, 4.00 mmol) andthiosemicarbazide (370 mg, 4.05 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.40 (s, 3H), 7.36-7.41 (m, 2H), 7.45(br s, 1H), 7.81-7.90 (m, 3H), 8.42 (br s, 1H), 10.56 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 43(599 mg, 90%) was obtained from1-(benzo[b]thiophen-2-yl)ethanone=thiosemicarbazone (500 mg, 2.01 mmol)prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.04 (s, 3H), 2.17 (s, 3H), 2.38 (s,3H), 7.31-7.40 (m, 3H), 7.79 (br d, J=7.6 Hz, 1H), 7.89 (br d, J=7.8 Hz,1H), 11.75 (br s, 1H)

Example 41 (Compound 44)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(3-thienyl)ethanone=thiosemicarbazone (839 mg, 98%) was obtained from3-acetylthiophene (520 mg, 4.12 mmol) and thiosemicarbazide (366 mg,4.00 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.27 (s, 3H), 7.52 (br d, J=5.3 Hz,1H), 7.83 (br d, J=5.3 Hz, 1H), 7.95 (br s, 1H), 8.22 (br s, 1H), 10.08(br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 44(540 mg, 83%) was obtained from 1-(3-thienyl)ethanone=thiosemicarbazone(458 mg, 2.30 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.02 (s, 3H), 2.15 (s, 3H), 2.25 (s,3H), 7.05 (br d, J=6.0 Hz, 1H), 7.37 (br s, 1H), 7.47 (br d, J=6.0 Hz,1H)

Example 42 (Compound 45)

Step 1: In a manner similar to that in Step 1 of Example 1,1-(2-thiazolyl)ethanone=thiosemicarbazone (711 mg, 90%) was obtainedfrom 2-acetylthiazole (379 mg, 4.15 mmol) and thiosemicarbazide (366 mg,4.00 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (s, 3H), 7.67 (br s, 1H), 7.79(br d, J=4.3 Hz, 1H), 7.87 (br d, J=4.3 Hz, 1H), 8.51 (br s, 1H), 10.65(br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 45(374 mg, 45%) was obtained from1-(2-thiazolyl)ethanone=thiosemicarbazone (374 mg, 1.87 mmol) preparedabove.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.03 (s, 3H), 2.18 (s, 3H), 2.31 (s,3H), 7.74-7.79 (m, 2H), 11.70 (br s, 1H)

Example 43 (Compound 46)

In a manner similar to that in Step 1 and 2 of Example 1, Compound 46(141 mg, 10%) was obtained from 2′-methylacetophenone (627 mg, 4.67mmol) and thiosemicarbazide (374 mg, 4.09 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.99 (br s, 1H), 2.21 (s, 3H), 2.33 (s,3H), 2.38 (s, 3H), 7.15-7.20 (m, 3H), 7.38 (m, 1H), 8.90 (br s, 1H)

Example 44 (Compound 47)

Step 1: In a manner similar to that in Step 1 of Example 1,3′-methylacetophenone=thiosemicarbazone (791 mg, 89%) was obtained from3′-methylacetophenone (540 mg, 4.02 mmol) and thiosemicarbazide (369 mg,4.04 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 47(316 mg, 79%) was obtained from 3′-methylacetophenone=thiosemicarbazone(300 mg, 1.36 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.23 (s, 3H), 2.34 (s,3H), 2.37 (s, 3H), 7.01-7.09 (m, 1H), 7.19-7.30 (m, 3H), 7.90 (br s, 1H)

Example 45 (Compound 48)

Step 1: In a manner similar to that in Step 1 of Example 1,4′-methylacetophenone=thiosemicarbazone (767 mg, 93%) was obtained from4′-methylacetophenone (536 mg, 3.99 mmol) and thiosemicarbazide (382 mg,4.19 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.27 (s, 3H), 2.32 (s, 3H), 7.18 (d,J=7.9 Hz, 2H), 7.82 (d, J=7.9 Hz, 2H), 7.88 (br s, 1H), 8.23 (br s, 1H),10.15 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 48(224 mg, 80%) was obtained from 4′-methylacetophenone=thiosemicarbazone(200 mg, 0.965 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.06 (s, 3H), 2.24 (s, 3H), 2.31 (s,3H), 2.36 (s, 3H), 7.13 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 8.40(br s, 1H)

Example 46 (Compound 49)

Step 1: In a manner similar to that in Step 1 of Example 1,2′-ethylpropiophenone=thiosemicarbazone (672 mg, 71%) was obtained from2′-ethylpropiophenone (649 mg, 4.00 mmol) and thiosemicarbazide (378 mg,4.14 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 49(759 mg, 88%) was obtained from 2′-ethylpropiophenone=thiosemicarbazone(300 mg, 1.27 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=6.9 Hz, 3H), 1.24 (t, J=7.3Hz, 3H), 1.96 (s, 3H), 2.20 (m, 1H), 2.24 (s, 3H), 2.71 (m, 2H), 3.14(m, 1H), 7.13 (br t, J=7.1 Hz, 1H), 7.21-7.26 (m, 2H), 7.51 (br d, J=7.9Hz, 1H), 8.87 (br s, 1H)

Example 47 (Compound 50)

Step 1: In a manner similar to that in Step 1 of Example 1,2′-methoxyacetophenone=thiosemicarbazone (891 mg, 92%) was obtained from2′-methoxyacetophenone (601 mg, 4.00 mmol) and thiosemicarbazide (366mg, 4.00 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 50(64.0 mg, 93%) was obtained from2′-methoxyacetophenone=thiosemicarbazone (50.0 mg, 0.224 mmol) preparedabove.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.08 (s, 3H), 2.29 (s, 3H), 2.45 (s,3H), 3.87 (s, 3H), 6.90 (br t, J=7.3 Hz, 1H), 6.91 (br d, J=7.3 Hz, 1H),7.06 (br d, J=7.3 Hz, 1H), 7.27 (br t, J=7.3 Hz, 1H), 8.31 (br s, 1H)

Example 48 (Compound 51)

Step 1: In a manner similar to that in Step 1 of Example 1,3′-methoxyacetophenone=thiosemicarbazone (713 mg, 58%) was obtained from3′-methoxyacetophenone (601 mg, 4.00 mmol) and thiosemicarbazide (377mg, 4.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.29 (s, 311), 3.80 (s, 3H), 6.96 (brd, J=7.9 Hz, 1H), 7.30 (br t, J=7.9 Hz, 111), 7A4 (br s, 111), 7.46 (brd, J=7.9 Hz, 1H), 7.94 (br s, 1H), 8.28 (br s, 1H), 10.18 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 51(419 mg, 71%) was obtained from 3′-methoxyacetophenone=thiosemicarbazone(500 mg, 2.24 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.10 (s, 311), 2.30 (s, 3H), 2.34 (s,3H), 3.78 (s, 3H), 6.78 (br d, J=7.9 Hz, 1H), 6.94 (br s, 1H), 7.01 (brd, J=7.9 Hz, 1H), 7.25 (br t, J=7.9 Hz, 1H), 9.48 (br s, 1H)

Example 49 Compound 52

Step 1: In a manner similar to that in Step 1 of Example 1,4′-methoxyacetophenone=thiosemicarbazone (448 mg, 83%) was obtained from4′-methoxyacetophenone (362 mg, 2.41 mmol) and thiosemicarbazide (225mg, 2.46 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 52(248 mg, 90%) was obtained from4′-methoxyacetophenone=thiosexnicarbazone (200 mg, 0.896 mmol) preparedabove.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.06 (s, 3H), 2.24 (a, 3H), 2.35 (s,3H), 3.78 (s, 3H), 6.84 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 8.56(br s, 1H)

Example 50 Compound 53

Step 1: In a manner similar to that in Step 1 of Example 1,2′-fluoroacetophenone=thiosemicarbazone (704 mg, 83%) was obtained from2′-fluoroacetophenone (558 mg, 4.04 mmol) and thiosemicarbazide (385 mg,4.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.29 (s, 3H), 7.19-7.28 (m, 2H),7.40-7.48 (m, 1H), 7.74-7.80 (m, 2H), 8.30 (br s, 1H), 10.34 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 53(199 mg, 71%) was obtained from 2′-fluoroacetophenone=thiosemicarbazone(200 mg, 0.948 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.05 (s, 3H), 2.26 (s, 3H), 2.40 (s,3H), 7.01-7.12 (m, 2H), 7.23-7.31 (m, 2H), 8.68 (br s, 1H)

Example 51 Compound 54

Step 1: In a manner similar to that in Step 1 of Example 1,3′-fluoroacetophenone=thiosemicarbazone (772 mg, 92%) was obtained from3′-fluoroacetophenone (553 mg, 4.00 mmol) and thiosemicarbazide (372 mg,4.07 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.29 (s, 3H), 7.17-7.24 (m, 1H),7.38-7.46 (m, 1H), 7.69 (br d, J=8.9 Hz, 1H), 7.88 (br d, J=11.2 Hz,1H), 8.09 (br s, 1H), 8.31 (br s, 1H), 10.24 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 54(242 mg, 74%) was obtained from 3′-fluoroacetophenone=thiosemicarbazone(233 mg, 1.10 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.08 (s, 3H), 2.26 (s, 3H), 2.35 (s,3H), 6.92-6.99 (m, 1H), 7.07-7.13 (m, 1H), 7.18-7.22 (m, 1H), 7.28-7.34(m, 1H), 8.54 (br s, 1H)

Example 52 Compound 55

Step 1: In a manner similar to that in Step 1 of Example 1,4′-fluoroacetophenone=thiosemicarbazone (769 mg, 91%) was obtained from4′-fluoroacetophenone (553 mg, 4.00 mmol) and thiosemicarbazide (376 mg,4.11 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 55(251 mg, 86%) was obtained from 4′-fluoroacetopbenone=thiosemicarbazone(208 mg, 0.986 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.14 (s, 3H), 2.22 (s, 3H), 2.36 (s,3H), 6.98-7.05 (m, 2H), 7.38-7.44 (m, 2H), 8.09 (br s, 1H)

Example 53 Compound 56

Step 1: In a manner similar to that in Step 1 of Example 1,2′-chloroacetophenone=thiosemicarbazone (362 mg, 58%) was obtained from2′-chloroacetophenone (344 mg, 2.23 mmol) and thiosemicarbazide (194 mg,2.12 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 56(347 mg, 97%) was obtained from 2′-chloroacetophenone=thiosemicarbazone(200 mg, 1.14 mmol) prepared above.

¹NMR (270 MHz, CDCl₃) δ (ppm): 1.98 (s, 3H), 2.23 (s, 3H), 2.38 (s, 3H),7.22-7.27 (m, 2H), 7.37-7.45 (m, 2H), 9.05 (br s, 1H)

Example 54 Compound 57

In a manner similar to that in Example 8, Compound 57 (347 mg, 97%) wasobtained from Compound 56 (200 mg, 1.14 mmol) prepared in Example 53.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.35 (t, J=6.9 Hz, 3H), 2.25 (s, 3H),2.30 (s, 3H), 2.40 (s, 3H), 3.91-3.93 (br s, 2H), 7.22-7.28 (m, 2H),7.38-7.42 (m, 2H)

Example 55 Compound 58

Step 1: In a manner similar to that in Step 1 of Example 1,3′-chloroacetophenone=thiosemicarbazone (211 mg, 45%) was obtained from3′-chloroacetophenone (319 mg, 2.06 mmol) and thiosemicarbazide (188 mg,2.06 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 58(347 mg, 97%) was obtained from 3′-chloroacetophenone=thiosemicarbazone(200 mg, 1.14 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.19 (s, 3H), 2.25 (s,3H), 7.29-7.41 (m, 4H), 11.68 (br s, 1H)

Example 56 Compound 59

Step 1: In a manner similar to that in Step 1 of Example 1,4′-chloroacetophenone=thiosemicarbazone (362 mg, 58%) was obtained from4′-chloroacetophenone (344 mg, 2.23 mmol) and thiosemicarbazide (194 mg,2.06 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 59(193 mg, 86%) was obtained from 4′-chloroacetophenone=thiosemicarbazone(164 mg, 0.720 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.11 (s, 3H), 2.23 (s, 3H), 2.24 (s,3H), 7.30 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 8.34 (br s, 1H)

Example 57 Compound 60

Step 1: In a manner similar to that in Step 1 of Example 1,2′-bromoacetophenone=thiosemicarbazone (392 mg, 69%) was obtained from2′-bromoacetophenone (415 mg, 2.08 mmol) and thiosemicarbazide (190 mg,2.08 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.28 (s, 3H), 7.29-7.76 (m, 5H), 8.25(br s, 1H), 10.35 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 60(328 mg, 99%) was obtained from 2′-bromoacetophenone=thiosemicarbazone(254 mg, 0.933 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.23 (s, 3H), 2.38 (s,3H), 7.13 (br t, J=7.6 Hz, 1H), 7.30 (br t, J=7.6 Hz, 1H), 7.47 (br d,J=7.6 Hz, 1H), 7.62 (br s, J=7.6 Hz, 1H), 8.86 (br s, 1H)

Example 58 Compound 61

Step 1: In a manner similar to that in Step 1 of Example 1,2′-hydroxyacetophenone=thiosemicarbazone (649 mg, 78%) was obtained from2′-hydroxyacetophenone (544 mg, 4.00 mmol) and thiosemicarbazide (377mg, 4.12 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.31 (s, 3H), 6.85 (br t, J=7.0 Hz,1H), 6.88 (br d, J=7.0 Hz, 1H), 7.25 (br t, J=7.0 Hz, 1H), 7.50 (br s,1H), 7.53 (br d, J=7.0 Hz, 1H), 7.81 (br s, 1H), 8.10 (br s, 1H), 10.35(br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 61(322 mg, 70%) was obtained from 2″-hydroxyacetophenone=thiosemicarbazone(233 mg, 1.10 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.04 (s, 3H), 2.06 (s, 3H), 2.23 (s,3H), 2.24 (s, 3H), 7.12 (br d, J=7.6 Hz, 1H), 7.23 (br t, J=7.6 Hz, 1H),7.35 (br t, J=7.6 Hz, 1H), 7.39 (br d, J=7.6 Hz, 1H), 10.20 (br s, 1H)

Example 59 Compound 62

Step 1: In a manner similar to that in Step 1 of Example 1,3′-hydroxyacetophenone=thiosemicarbazone (654 mg, 78%) was obtained from3′-hydroxyacetophenone (546 mg, 4.01 mmol) and thiosemicarbazide (379mg, 4.15 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 62(351 mg, 84%) was obtained from 3′-hydroxyacetophenone=thiosemicarbazone(262 mg, 1.25 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.96 (s, 3H), 2.27 (s, 3H), 2.28 (s,3H), 2.34 (s, 3H), 7.07 (br d, J=8.4 Hz, 1H), 7.15 (br s, 1H), 7.32 (brd, J=8.4 Hz, 1H), 7.33 (br t, J=8.4 Hz, 1H), 9.24 (br s, 1H)

Example 60 Compound 63

Step 1: In a manner similar to that in Step 1 of Example 1,3′-hydroxybenzaldehyde=thiosemicarbazone (732 mg, 88%) was obtained from3′-hydroxybenzaldehyde (488 mg, 4.00 mmol) and thiosemicarbazide (378mg, 4.15 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 6.80 (m, 1H), 7.13 (br s, 1H), 7.19(m, 2H), 7.87 (br s, 1H), 7.96 (s, 1H), 8.14 (br s, 1H), 9.66 (br s,1H), 11.35 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 63(322 mg, 70%) was obtained from 3′-hydroxybenzaldehyde=thiosemicarbazone(300 mg, 1.43 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.18 (s, 3H), 2.25 (s, 3H), 2.28 (s,3H), 6.86 (s, 1H), 7.04 (br d, J=7.4 Hz, 1H), 7.05 (s, 1H), 7.19 (br d,J=7.4 Hz, 1H), 7.31 (br t, J=7.4 Hz, 1H), 8.16 (br s, 1H)

Example 61 Compound 64

Step 1: In a manner similar to that in Step 1 of Example 1,4′-hydroxyacetophenone=thiosemicarbazone (830 mg, 99%) was obtained from4′-hydroxyacetophenone (544 mg, 4.00 mmol) and thiosemicarbazide (387mg, 425 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.23 (s, 3H), 6.75 (d, J=8.5 Hz, 2H),7.76 (d, J=8.5 Hz, 2H), 7.78 (br s, 1H), 8.14 (br s, 1H), 9.75 (s, 1H),10.05 (s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 64(199 mg, 61%) was obtained from 4′-hydroxyacetophenone=thiosemicarbazone(202 mg, 0.965 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.22 (s, 3H), 2.23 (s,3H), 2.29 (s, 3H), 7.07 (br d, J=8.6 Hz, 2H), 7.43 (br d, J=8.6 Hz, 2H),7.99 (br s, 1H)

Example 62 Compound 65

Step 1: In a manner similar to that in Step 1 of Example 1,2′-nitroacetophenone=thiosemicarbazone (785 mg, 81%) was obtained from2′-nitroacetophenone (673 mg, 4.08 mmol) and thiosemicarbazide (365 mg,3.99 mmol).

1H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.27 (s, 3H), 7.32 (br s, 1H),7.60-7.68 (m, 1H), 7.72-7.79 (m, 2H), 7.96 (br d, J=7.9 Hz, 1H), 8.31(br s, 1H), 10.52 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 65(548 mg, 94%) was obtained from 2′-nitroacetophenone=thiosemicarbazone(431 mg, 1.81 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.04 (s, 3H), 2.07 (s, 3H), 2.23 (s,3H), 7.49-7.71 (m, 4H), 11.73 (br s, 1H)

Example 63 Compound 66

Step 1: In a manner similar to that in Step 1 of Example 1,3′-nitroacetophenone=thiosemicarbazone (910 mg, 75%) was obtained from3′-nitroacetophenone (661 mg, 4.00 mmol) and thiosemicarbazide (370 mg,4.05 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.37 (s, 3H), 7.67 (br t, J=7.9 Hz,1H), 8.16 (br s, 1H), 8.23 (br d, J=7.9 Hz, 1H), 8.40 (br s, 1H), 8.43(br s, J=7.9 Hz, 1H), 8.61 (br s, 1H), 10.40 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 66(409 mg, 60%) was obtained from 3′-nitroacetophenone=thiosemicarbazone(606 mg, 2.12 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.25 (s, 3H), 2.40 (s,3H), 7.53 (br t, J=8.3 Hz, 1H), 7.73 (br d, J=8.3 Hz, 1H), 8.15 (br d,J=8.3 Hz, 1H), 8.30 (br s, 2H)

Example 64 Compound 67

Step 1: In a manner similar to that in Step 1 of Example 1,4′-nitroacetophenone=thiosemicarbazone (475 mg, 94%) was obtained from4′-nitroacetophenone (350 mg, 2.12 mmol) and thiosemicarbazide (195 mg,2.13 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 67(216 mg, 40%) was obtained from 4′-nitroacetophenone=thiosemicarbazone(397 mg, 1.67 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.24 (s, 3H), 2.38 (s,3H), 7.59 (d, J=8.6 Hz, 2H), 8.20 (d, J=8.6 Hz, 2H), 8.30 (br s, 1H)

Example 65 Compound 68

Compound 61 (118 mg, 0.352 mmol) prepared in Example 58 was dissolved inmethanol (5 mL), and to the solution was added potassium carbonate (200mg, 1.48 mmol) and the mixture was stirred at room temperature for 10minutes. The reaction mixture was filtered, and the filtrate wasconcentrated under reduced pressure. After the residue was dissolved inethyl acetate, to the solution was added water and 1 mol/L hydrochloricacid, and the mixture was subjected to separation. The organic layer waswashed with saturated aqueous sodium chloride and dried over anhydroussodium sulfate, and then the solvent was evaporated under reducedpressure. The resulting yellow oil was dissolved in methanol (3 mL). Tothe solution was added diisopropyl ether (10 mL), and the depositedcrystals were collected by filtration and dried to obtain Compound 68(96.9 mg, 94%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.98 (s, 3H), 2.23 (s, 3H), 2.35 (s,3H), 6.72 (br t, J=7.6 Hz, 1H), 6.83 (br d, J=7.6 Hz, 1H), 6.88 (br d,J=7.6 Hz, 1H), 7.10 (br t, J=7.6 Hz, 1H), 9.95 (br s, 1H), 11.45 (br s,1H)

Example 66 Compound 69

In a manner similar to that in Example 65, Compound 69 (101 mg, 82%) wasobtained from Compound 62 (140 mg, 0.417 mmol) prepared in Example 59.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 2.23 (s,3H), 6.66 (br t, J=7.9 Hz, 1H), 6.69 (br s, 1H), 6.76 (br d, J=7.9 Hz,1H), 7.13 (br t, J=7.9 Hz, 1H), 9.46 (br s, 1H), 11.60 (br s, 1H)

Example 67 Compound 70

In a manner similar to that in Example 65, Compound 70 (88 mg, 91%) wasobtained from Compound 64 (110 mg, 0.328 mmol) prepared in Example 61.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.00 (s, 3H), 2.16 (s, 3H), 2.23 (s,3H), 6.71 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 9.48 (br s, 1H),11.6 (br s, 1H).

Example 68 Compound 71

Step 1: In a manner similar to that in Step 1 of Example 1,3′-cyanoacetophenone=thiosemicarbazone (863 mg, 99%) was obtained from3-acetylbenzonitrile (581 mg, 4.00 mmol) and thiosemicarbazide (370 mg,4.05 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 71(274 mg, 68%) was obtained from 3′-cyanoacetophenone=thiosemicarbazone(300 mg, 1.34 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.08 (s, 3H), 2.26 (s, 3H), 2.36 (s,3H), 7.46 (m, 1H), 7.56 (m, 1H), 7.68 (m, 1H), 7.71 (br s, 1H), 8.73 (brs, 1H)

Example 69 Compound 72

Step 1: In a manner similar to that in Step 1 of Example 1,4′-cyanoacetophenone=thiosemicarbazone (430 mg, 98%) was obtained from4-acetylbenzonitrile (290 mg, 2.0 mmol) and thiosemicarbazide (185 mg,2.02 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.30 (s, 3H), 7.82 (d, J=8.4 Hz, 2H),8.12 (br s, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.40 (br s, 1H), 10.51 (br s,1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 72(494 mg, 94%) was obtained from 4′-cyanoacetophenone=thiosemicarbazone(380 mg, 1.74 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 2.31 (s,3H), 7.54 (d, J=11.7 Hz, 2H), 7.81 (d, J=11.7 Hz, 2H), 11.73 (br s, 1H)

Example 70 Compound 73

Step 1: In a manner similar to that in Step 1 of Example 1,3′-trifluoromethylacetophenone=thiosemicarbazone (888 mg, 63%) wasobtained from 3′-trifluoromethylacetophenone (765 mg, 4.07 mmol) andthiosemicarbazide (370 mg, 4.05 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 73(270 mg, 68%) was obtained from3′-trifluoromethylacetophenone=thiosemicarbazone (300 mg, 1.15 mmol)prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.27 (s, 3H), 2.37 (s,3H), 7.43 (br t, J=7.6 Hz, 1H), 7.52 (br d, J=7.6 Hz, 1H), 7.63 (br d,J=7.6 Hz, 1H), 7.65 (br s, 1H), 8.89 (br s, 1H)

Example 71 Compound 74

Step 1: In a manner similar to that in Step 1 of Example 1,2′-carboxyacetophenone=thiosemicarbazone (489 mg, 52%) was obtained from2-acetylbenzoic acid (381 mg, 4.17 mmol) and thiosemicarbazide (381 mg,4.17 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 74(313 mg, 64%) was obtained from 2′-carboxyacetophenone=thiosemicarbazone(363 mg, 1.53 mmol) prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.04 (s, 3H), 2.29 (s, 3H), 2.38 (s,3H), 3.20-3.30 (br s, 1H), 4.88-8.15 (m, 3H), 8.32-8.33 (br m, 1H)

Example 72 Compound 75

Step 1: In a manner similar to that in Step 1 of Example 1,2′,6′-dimethoxyacetophenone=thiosemicarbazone (747 mg, 83%) was obtainedfrom 2′,6′-dimethoxyacetophenone (606 mg, 3.98 mmol) andthiosemicarbazide (374 mg, 4.09 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.09 (s, 3H), 3.77 (s, 6H), 6.80 (d,J=8.2 Hz, 2H), 7.44 (t, J=8.2 Hz, 1H), 7.83 (br s, 1H), 8.04 (br s, 1H),8.31 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 75(441 mg, 89%) was obtained from2′,6′-diraethoxyacetophenone=thiosemicarbazone (363 mg, 1.61 mmol)prepared above.

¹H NMR (270 MHz, CDCl₆) δ (ppm): 2.02 (s, 3H), 2.21 (s, 3H), 2.51 (s,3H), 3.78 (s, 6H), 6.53 (d, J=8.5 Hz, 2H), 7.15 (t, J=8.5 Hz, 1H), 8.70(br s, 1H)

Example 73 Compound 76

Step 1: In a manner similar to that in Step 1 of Example 1,3′,5′-dihydroxyacetophenone=thiosemicarbazone (707 mg, 78%) was obtainedfrom 3′,5′-dihydroxyacetophenone (613 mg, 4.03 mmol) andthiosemicarbazide (376 mg, 4.11 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.20 (s, 3H), 6.25 (br s, 1H), 6.69(br s, 2H), 7.64 (br s, 1H), 8.26 (br s, 1H), 9.29 (br s, 2H), 10.19 (brs, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 76(591 mg, 69%) was obtained from3′,5′-dihydroxyacetophenone=thiosemicarbazone (622 mg, 2.76 mmol)prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.17 (s, 3H), 2.18 (s,3H), 6.10 (br s, 1H), 6.16 (br s, 2H), 9.27 (br s, 2H), 11.59 (br s, 1H)

Example 74 Compound 77

Step 1: In a manner similar to that in Step 1 of Example 1,3′,4′-dihydroxyacetophenone=thiosemicarbazone (747 mg, 83%) was obtainedfrom 3′,4′-dihydroxyacetophenone (606 mg, 3.98 mmol) andthiosemicarbazide (374 mg, 4.09 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.20 (s, 3H), 6.72 (br d, J=8.3 Hz,1H), 7.18 (br d, J=8.3 Hz, 1H), 7.29 (br s, 1H), 7.65 (br s, 1H), 8.18(br s, 2H), 9.09 (br s, 2H), 10.09 (br s, 1H)

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 77(441 mg, 89%) was obtained from3′,4′-dihydroxyacetophenone=thioseraicarbazone (363 mg, 1.61 mmol)prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.01 (s, 3H), 2.06 (s, 3H), 2.20 (s,3H), 6.62 (br t, J=7.6 Hz, 1H), 6.66 (br d, J=8.2 Hz, 1H), 6.71 (br s,1H), 8.93 (s, 1H), 8.97 (s, 1H), 11.56 (br s, 1H)

Example 75 Compound 78

Step 1: In a manner similar to that in Step 1 of Example 1,2′,4′-dimethylacetophenone=thiosemicarbazone (110 mg, 12%) was obtainedfrom 2′,4′-dimethylacetophenone (598 mg, 4.04 mmol) andthiosemicarbazide (366 mg, 4.00 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 78(107 mg, 77%) was obtained from2′,4′-dimethylacetophenone=thiosemicarhazone (100 mg, 0.452 mmol)prepared above.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.16 (s, 3H), 2.21 (s, 3H), 2.35 (s,3H), 6.92 (d, J=7.9 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 8.22 (br s, 1H)

Example 76 Compound 79

Step 1: To a solution of hydrazine monohydrate (1.00 mL, 20.6 mmol) inacetonitrile (5.00 mL) was added allyl isothiocyanate (2.00 mL, 20.4mmol), and the mixture was stirred at 60° C. for 30 minutes. To thereaction mixture was added diethyl ether (50 mL), and the depositedsolid was collected by filtration. The collected solid was dried toobtain 4-allylthiosemicarbazide (1.22 g, 46%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 4.11 (t, J=5.3 Hz, 2H), 4.47 (br s,2H), 5.03 (d, J=12.3 Hz, 1H), 5.08 (d, J=19.1 Hz, 1H), 5.86 (m, 1H),7.88 (br s, 1H), 8.70 (br s, 1H)

Step 2: In a manner similar to that in Step 1 of Example 1,acetophenone=4-allylthiosemicarbazone (1.74 g, 80%) was obtained fromacetophenone (1.09 mL, 9.34 mmol) and 4-allylthiosemicarbazide (1.22 g,9.31 mmol) prepared above.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.31 (s, 3H), 4.25 (t, J=5.8 Hz, 2H),5.10 (d, J=10.5 Hz, 1H), 5.18 (d, J=17.5 Hz, 1H), 5.91 (m, 1H),7.37-7.42 (m, 3H), 7.91-7.94 (m, 2H), 8.61 (t, J=6.0 Hz, 1H), 10.3 (brs, 1H)

Step 3: Acetophenone=4-allylthiosemicarbazone (30 mg, 0.11 mmol)prepared above was dissolved in chloroform (0.5 mL), and to the solutionwas added acetyl chloride (0.17 mL, 2.32 mmol) and pyridine (0.190 mL,2.31 mmol), and the solution was stirred at room temperature for 5hours. To the reaction mixture was added 2 mol/L aqueous sodiumhydroxide, then the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous ammonium chloride andsaturated aqueous sodium chloride, and then dried over anhydrous sodiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography (ethyl acetate/n-hexane=1/2) to obtainCompound 79 (25 mg, 89%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.26 (s, 3H), 2.27 (s, 3H), 2.36 (s,3H), 4.47-4.53 (m, 2H), 5.24 (d, J=17.3 Hz, 1H), 5.29 (d, J=10.5 Hz,1H), 5.91 (m, 1H), 7.20-7.45 (m, 5H)

FAB-MS (m/z): 318 (M⁺+1)

Example 77 Compounds 80 and 81

Step 1: In a manner similar to that in Step 3 of Example 76, Compound 80(42 mg, 5%) was obtained from acetophenone=4-allylthiosemicarbazone (694mg, 2.97 mmol) prepared in Step 2 of Example 76, isobutyryl chloride(0.63 mL, 5.97 mmol) and pyridine (0.43 mL, 5.26 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.10 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.9Hz, 3H), 2.39 (s, 3H), 3.25 (quin., J=7.0 Hz, 1H), 3.84-4.00 (m, 3H),5.19 (d, J=10.2 Hz, 1H), 5.26 (d, J=17.2 Hz, 1H), 5.93 (m, 1H),7.20-7.49 (m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 81 (527 mg,74%) was obtained from Compound 80 (623 mg, 2.05 mmol) prepared above,acetyl chloride (0.59 mL, 8.30 mmol) and pyridine (0.77 mL, 8.28 mmol).

¹H NMR (270 MHz, CDCl₆) δ (ppm): 1.10 (d, J=6.9 Hz, 3H), 1.12 (d, J=6.9Hz, 3H), 2.27 (s, 3H), 2.34 (s, 3H), 3.21 (quin., J=6.9 Hz, 1H), 4.51(br s, 2H), 5.25 (d, J=17.2 Hz, 1H), 5.30 (d, J=10.7 Hz, 1H), 5.93 (m,1H), 7.20-7.42 (m, 5H)

AP-MS (m/z): 346 (M⁺+1)

Example 78 Compound 82

In a manner similar to that in Step 3 of Example 76, Compound 82 (269mg, 47%) was obtained from acetophenone=thiosemicarbazone (306 mg, 1.59mmol) prepared in Step 1 of Example 1, pivaloyl chloride (0.40 mL, 3.21mmol) and pyridine (0.26 mL, 3.22 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.30 (s, 9H), 2.35 (s,3H), 7.20-7.46 (m, 5H), 7.90 (m, 1H)

AP-MS (m/z): 360 (M⁺−1)

Example 79 Compounds 83 and 84

Step 1: In a manner similar to that in Example 12, Compound 83 (537 mg,67%) was obtained from Compound 21(1.00 g, 2.88 mmol) prepared inExample 18.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (d, J=6.9 Hz, 3H), 1.14 (d, J=6.9Hz, 3H), 2.39 (s, 3H), 2.91 (d, J=4.9 Hz, 3H), 3.30 (m, 1H), 3.90 (br,1H), 7.20-7.43 (m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 84 (233 mg,38%) was obtained from Compound 83 (536 mg, 1.93 mmol) prepared above,acetyl chloride (0.28 mL, 3.87 mmol) and pyridine (0.32 mL, 3.90 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (d, J=6.9 Hz, 3H), 1.14 (d, J=6.9Hz, 3H), 2.28 (s, 3H), 2.34 (s, 3H), 3.28 (quin., J=6.9 Hz, 1H), 3.46(br s, 3H), 7.20-7.43 (m, 5H)

FAB-MS (m/z): 320 (M⁺+1)

Elemental analysis (C₁₆H₂₁N₃O₂S): Found (%) C; 60.16, H; 6.63, N; 13.15,Calcd. (%) C; 60.27, H; 6.73, N; 13.20

Example 80 Compound 85

In a manner similar to that in Step 2 of Example 1, Compound 85 (176 mg,20%) was obtained from acetophenone=thiosemicarbazone (517 mg, 2.68mmol) prepared in Step 1 of Example 1 and isobutyric anhydride (2.22 mL,13.4 mmol).

¹H NMR (270 MHz, CDCl₃) δ ppm): 1.09 (d, J=2.6 Hz, 3H), 1.12 (d, J=2.6Hz, 3H), 1.21 (d, J=2.6 Hz, 3H), 1.23 (d, J=2.6 Hz, 3H), 2.37 (s, 3H),2.50 (quin., J=6.9 Hz, 1H), 3.20 (quin., J=6.9 Hz, 1H), 7.20-7.48 (m,5H), 7.98 (br s, 1H)

AP-MS (m/s): 334 (M⁺+1)

Elemental analysis (C₁₇H₂₃N₃O₂S): Found (%) C; 61.23, H; 6.95, N; 12.60,Calcd. (%) C; 61.22, H; 6.93, N; 12.63

Example 81 Compounds 86 and 87

Step 1: In a manner similar to that in Example 11, Compound 86 (588 mg,43%) was obtained from acetophenone=thiosemicarbazone (1.01 g, 5.22mmol) prepared in Step 1 of Example 1, isobutyric anhydride (1.73 mL,10.4 mmol) and pyridine (0.84 mL, 10.4 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.09 (d, J=6.9 Hz, 3H), 1.11 (d, J=6.9Hz, 3H), 2.40 (s, 3H), 3.21 (quin., J=6.9 Hz, 1H), 4.12 (br s, 2H),7.20-7.40 (m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 87 (47 mg,16%) was obtained from Compound 86 (256 mg, 0.97 mmol) prepared aboveand acetic anhydride (0.46 mL, 4.88 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.19 (d, J=6.9 Hz, 3H), 1.20 (d, J=6.9Hz, 3H), 2.25 (s, 3H), 2.38 (s, 3H), 2.47 (quin., J=6.9 Hz, 1H),7.20-7.50 (m, 5H)

Example 82 Compound 88

In a manner similar to that in Example 15, Compound 88 (53 mg, 8%) wasobtained from Compound 14 (502 mg, 2.14 mmol) prepared in Example 11 andisobutyric anhydride (1.77 mL, 10.7 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.20 (d, J=6.9 Hz, 3H), 1.22 (d, J=6.9Hz, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 2.48 (quin., J=6.9 Hz, 1H),7.20-7.46 (m, 5H), 8.08 (br s, 1H)

AP-MS (m/z): 306 (M⁺+1)

Example 83 Compound 89

In a manner similar to that in Example 15, Compound 89 (274 mg, 64%) wasobtained from Compound 14 (303 mg, 1.29 mmol) prepared in Example 11,cyclopentanecarbonyl chloride (0.32 mL, 2.59 mmol) and pyridine (0.21mL, 2.60 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.50-1.95 (m, 8H), 2.24 (s, 3H), 2.38(s, 3H), 2.65 (quin., J=7.9 Hz, 1H), 7.20-7.45 (m, 5H), 8.04 (br s, 1H)

AP-MS (m/z): 330 (M⁺−1)

Elemental analysis (C₁₇H₂₁N₃O₂S.0.4H₂O): Found (%) C; 60.30, H; 6.49, N;12.41, Calcd. (%) C; 60.45, H; 6.49, N; 12.05

Example 84 Compounds 90 and 91

Step 1: In a manner similar to that in Example 11, Compound 90 (123 mg,13%) was obtained from acetophenone=thiosemicarbazone (507 mg, 2.63mmol) prepared in Step 1 of Example 1, isovaleric anhydride (1.05 mL,5.30 mmol) and pyridine (0.43 mL, 5.26 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.82-1.00 (m, 6H), 2.12 (quin., J=6.6Hz, 1H), 2.38 (s, 3H), 2.45 (d, J=7.7 Hz, 2H), 4.34 (br, 2H), 7.20-7.48(m, 5H)

Step 2: In a manner similar to that in Example 15, Compound 91 (128 mg,98%) was obtained from Compound 91 (105 mg, 0.38 mmol) prepared above,isobutyryl chloride (0.08 mL, 0.76 mmol) and pyridine (0.06 mL, 0.80mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.92 (d, J=6.6 Hz, 1H), 0.93 (d, J=6.6Hz, 1H), 1.18 (d, J=3.3 Hz, 1H), 1.21 (d, J=3.3 Hz, 1H), 2.13 (quin.,J=6.6 Hz, 1H), 2.38 (s, 3H), 2.39-2.56 (m, 4H), 7.20-7.48 (m, 5H), 8.15(br s, 1H)

Example 85 Compound 92

Step 1: To a solution of acetophenone (4.00 mL, 34.3 mmol) in ethanol(15 mL) was added hydrazine monohydrate (6.67 mL, 138 mmol), and themixture was heated under reflux for 4 hours. After cooling, to themixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, and then dried over anhydrous sodium sulfate, and the solventwas evaporated. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=1/2) to obtainacetophenone=hydrazone (5.39 g, ˜100%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.00 (s, 3H), 5.34 (br s, 2H),7.22-7.60 (m, 5H)

¹³C NMR (300 MHz, CDCl₃) δ (ppm): 11.3, 125.1, 127.7, 127.9, 139.1,146.7

Step 2: To a solution of ammonium thiocyanate (3.40 g, 44.6 mmol) inacetone (20 mL) was added acetyl chloride (2.80 mL, 37.1 mmol), and themixture was stirred at 70° C. for 10 minutes. To the reaction mixturewas added acetophenone=hydrazone (5.36 g, 40.0 mmol) prepared above, andthe mixture was heated under reflux for 20 minutes. After the reactionmixture was cooled, saturated aqueous ammonium chloride was added to themixture, and the mixture was extracted with chloroform. The organiclayer was washed with saturated aqueous sodium chloride, and then driedover anhydrous sodium sulfate, and the solvent was evaporated. Theresidue was purified by silica gel column chromatography (ethylacetate/n-hexane=1/2) to obtain acetophenone=4-acetylthiosemicarbazone(148 mg, 2%).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.15 (s, 3H), 2.28 (s, 3H), 7.47-7.51(m, 3H), 7.56-7.59 (m, 2H), 11.6 (br s, 1H), 13.6 (br s, 1H)

Step 3: In a manner similar to that in Step 3 of Example 76, Compound 92(36 mg, 88%) was obtained from acetophenone=4-acetylthiosemicarbazone(30 mg, 0.13 mmol) prepared above, pivaloyl chloride (32 μL, 0.26 mmol)and pyridine (20 μL, 0.26 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.25 (s, 3H), 2.38 (s,3H), 7.23-7.46 (m, 5H), 8.13 (br s, 1H)

¹³C NMR (300 MHz, CDCl₃) δ (ppm): 24.0, 27.2, 39.4, 80.5, 125.1, 128.0,128.6, 143.0, 143.1, 169.0, 176.7

AP-MS (m/z): 318 (M⁺+1)

Example 86 Compound 93

In a manner similar to that in Step 2 of Example 1, Compound 93 (123 mg,45%) was obtained from Compound 14 (201 mg, 0.853 mmol) prepared inExample 11 and pivaloyl chloride (0.21 mL, 1.71 mmol)

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.26 (s, 9H), 2.24 (s, 3H), 2.38 (s,3H), 7.20-7.51 (m, 5H), 8.10 (br s, 1H)

AP-MS (m/z): 319 (M⁺+1)

Example 87 Compound 94

Step 1: In a manner similar to that in Step 1 of Example 1,propiophenone=thiosemicarbazone (759 mg, 88%) was obtained frompropiophenone (382 mg, 4.18 mmol) and thiosemicarbazide (541 mg, 3.92mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 94(270 mg, 58%) was obtained from propiophenone=thiosemicarbazone (256 mg,1.24 mmol) prepared above, pivaloyl chloride (597 μL, 4.84 mmol) andpyridine (391 μL, 4.84 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.15 (dd, J=7.1, 7.3 Hz, 3H), 1.29 (s,9H), 1.34 (s, 9H), 2.29 (qd, J=7.3, 14.6 Hz, 1H), 3.10 (qd, J=7.1, 14.6Hz, 1H), 7.21-7.40 (m, 5H), 8.31 (br s, 1H)

AP-MS (m/z): 377 (M⁺+1)

Example 88 Compound 95

Step 1: 2-Aminoacetophenone hydrochloride (6.10 g, 35.5 mmol) wasdissolved in dichloromethane (60 mL), and to the solution was addedtriethylamine (7.56 g, 74.9 mmol). The solution was cooled to 0° C., andto the solution was added methanesulfonyl chloride (2.84 mL, 36.5 mmol).The solution was stirred at the same temperature for 5 minutes, and thenat room temperature for 2 hours. To the reaction mixture was added waterand 1 mol/L hydrochloric acid, and the mixture was extracted withchloroform. After the organic layer was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure. The residuewas suspended in chloroform (5 mL) and the suspension was stirred, andthen, the resulted crystals were collected by filtration to obtain2-(methylsulfonylamino)acetophenone (4.58 g, 57%).

Step 2: In a manner similar to that in Step 1 of Example 1,2-(methylsulfonylamino)acetophenone=thiosemicarbazone (3.08 g, 51%) wasobtained from 2-(methylsulfonylamino)acetophenone (4.58 g, 20.2 mmol)prepared above and thiosemicarbazide (1.84 g, 20.2 mmol).

Step 3: In a manner similar to that in Step 3 of Example 76, Compound 95(1.81 g, 91%) was obtained from2-(methylsulfonylamino)acetoplienone=thiosemicarbazone (1.31 g, 4.36mmol) prepared above, pivaloyl chloride (2.10 g, 17.4 mmol) and pyridine(1.38 g, 17.4 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 1.36 (s, 9H), 2.97 (s,3H), 3.98 (dd, J=5.3, 13.8 Hz, 1H), 4.64 (dd, J=8.5, 13.8 Hz, 1H), 5.10(br dd, J=5.3, 8.5 Hz, 1H), 7.25-7.39 (m, 5H), 7.93 (br s, 1H)

AP-MS (m/z): 453 (M⁺−1)

Example 89 Compound 96

Step 1: In a manner similar to that in Step 1 of Example 1,2-(methylsulfonylamino)acetophenone=4-methylthiosemicarbazone (122 mg)was obtained from 2-(methylsulfonylamino)acetophenone (209 mg, 0.98mmol) prepared in Step 1 of Example 88 and 4-methylthiosemicarbazide(106 mg, 1.00 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound 96(68 mg, 15%) was obtained from2-(methylsulfonylamino)acetophenone=4-methylthiosemicarbazone (122 mg,0.41 mmol) obtained above, pivaloyl chloride (128 μL, 1.04 mmol) andpyridine (80 μL, 1.04 mmol).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 1.27 (s, 3H), 1.28 (s, 3H), 2.95 (s,3H), 3.53 (s, 3H), 3.94 (dd, J=13.9, 6.4 Hz, 1H), 4.27 (dd, J=13.9, 7.9Hz, 1H), 7.11 (t, J=7.2 Hz, 1H), 7.21-7.38 (m, 5H)

AP-MS (m/z): 467 (M⁺−1)

Example 90 Compound 97

Step 1: In a manner similar to that in Step 1 of Example 88,2-(ethylsulfonylamino)acetophenone (367 mg, 39%) was obtained from2-aminoacetophenone hydrochloride (714 mg, 4.16 mmol), triethylamine(1.45 mL, 10.4 mmol) and ethanesulfonyl chloride (0.434 mL, 4.58 mmol).

Step 2: In a manner similar to that in Step 1 of Example 1,2-(ethylsulfonylamino)acetophenone=thiosemicarbazone (327 mg, 43%) wasobtained from 2-(ethylsulfonylamino)acetophenone (367 mg, 1.61 mmol)prepared above and thiosemicarbazide (147 mg, 1.61 mmol).

Step 3: In a manner similar to that in Step 2 of Example 1, Compound 97(39 mg, 25%) was obtained from2-(ethylsulfonylamino)acetophenone=thiosemicarbazone (99 mg, 0.330mmol), pivaloyl chloride (162 μL, 1.32 mmol) and pyridine (130 μL, 1.58mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.26 (s, 9H), 1.28 (t, J=7.8 Hz, 3H),1.29 (s, 9H), 3.09 (m, 2H), 3.97 (dd, J=5.1, 13.5 Hz, 1H), 4.60 (dd,J=8.1, 13.5 Hz, 1H), 4.99 (br dd, J=5.1, 8.1 Hz, 1H), 7.25-7.38 (br s,5H), 7.93 (br s, 1H)

Example 91 Compound 98

Step 1: In a manner similar to that in Step 1 of Example 1,2-methoxyacetophenone=thiosemicarbazone (367 mg, 62%) was obtained from2-methoxyacetophenone (288 mg, 1.92 mmol) and thiosemicarbazide (179 mg,1.96 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 98(132 mg, 59%) was obtained from 2-methoxyacetophenone=thiosemicarbazone(128 mg, 0.573 mmol) prepared above, pivaloyl chloride (211 μL, 1.72mmol) and pyridine (152 μL, 1.88 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.28 (s, 9H), 1.32 (s, 9H), 3.51 (s,3H), 4.36 (d, J=9.6 Hz, 1H), 4.48 (d, J=9.6 Hz, 1H), 7.24-7.38 (m, 5H),7.88 (s, 1H)

AP-MS (m/z): 392 (M⁺+1)

Example 92 Compound 99

Step 1: Methane sulfonamide (0.476 g, 5.00 mmol) was dissolved inN,N-dimethylformamide (10 mL), and to the solution was added 60% sodiumhydride (0.275 g, 5.00 mmol) and the mixture was stirred in a water bathfor 20 minutes. To the reaction mixture was added 3-chloropropiophenone(843 mg, 5.00 mol). The mixture was stirred in a water bath for onehour, and further stirred at room temperature for 15 hours. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride and dried over anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (chloroform/methanol=20/1) to obtain3-(methylsulfonylamino)propiophenone (240 mg, 21%).

Step 2: In a manner similar to that in Step 1 of Example 1,3-(methylsulfonylamino)propiophenone=thiosemicarbazone (219 mg, 45%) wasobtained from 3-(methylsulfonylamino)propiophenone (388 mg, 1.71 mmol)prepared above and thiosemicarbazide (156 mg, 1.71 mmol).

Step 3: In a manner similar to that in Step 2 of Example 1, Compound 99(218 mg, 86%) was obtained from3-(methylsulfonylamino)propiophenone=thiosemicarbazone (200 mg, 0.696mmol) obtained above, pivaloyl chloride (342 μL, 2.78 mmol) and pyridine(219 μL, 2.78 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 1.34 (s, 9H), 2.56-2.65(m, 1H), 2.94 (s, 3H), 3.21-3.44 (m, 2H), 3.58-3.70 (m, 1H), 4.45 (br s,1H), 7.28-7.37 (m, 5H), 7.97 (br s, 1H)

AP-MS (m/z): 467 (M−1)

Example 93 Compound 100

In a manner similar to that in Step 3 of Example 76, an oily compoundwas obtained from 3-(methylsulfonylamino)propiophenone=thiosemicarbazone(173 mg, 0.604 mmol) prepared in Step 2 of Example 92, isobutyrylchloride (316 μL 3.02 mmol) and pyridine (292 μL, 3.62 mmol). The oilycompound was dissolved in methanol (10 mL). To the solution was addedpotassium carbonate (1.00 g, 7.24 mind), and the mixture was vigorouslystirred for 1 hour. The reaction mixture was filtered, and the filtratewas concentrated. And then, to the concentrate was added chloroform,water and 1.0 mol/L hydrochloric acid, and the solution was extractedwith chloroform. The organic layer was washed with saturated aqueoussodium chloride, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bypreparative thin layer chromatography (chloroform/methanol=20/1) toobtain Compound 100 (111 mg, 41%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 0.99-1.07 (m, 12H), 2.55-2.66 (m,2H), 2.80-3.00 (m, 1H), 2.89 (s, 3H), 3.05-3.17 (m, 1H), 3.24-3.38 (m,2H), 7.15 (br t, J=5.9 Hz, 1H), 7.24-7.39 (m, 5H), 11.6 (br s, 1H)

Example 94 Compound 101

Step 1: In a manner similar to that in Step 1 of Example 88,2-(trifluoroacetylamino)acetophenone (4.38 g, 59%) was obtained from2-aminoacetophenone hydrochloride (5.47 g, 31.9 mmol), triethylamine(11.1 mL, 80.0 mmol) and trifluoroacetic anhydride (4.96 mL, 35.1 mmol).

Step 2: In a manner similar to that in Step 1 of Example 1,2-(trifluoroacetylamino)acetophenone=thiosemicarbazone was obtained from2-(trifluoroacetylamino)acetophenone (3.00 g, 13.0 mmol) prepared aboveand thiosemicarbazide (1.18 g, 13.0 mmol).

Step 3: In a manner similar to that in Step 3 of Example 76, Compound101 (1.72 g, 28%) was obtained from2-(trifluoroacetylamino)acetophenone=thiosemicarbazone prepared above,pivaloyl chloride (50 mmol, 6.16 mL) and pyridine (60.0 mmol, 4.85 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 1.38 (s, 9H), 3.95 (dd,J=3.0, 13.5 Hz, 1H), 4.89 (dd, J=3.7, 13.5 Hz, 1H), 7.15 (br d, J=7.3Hz, 2H), 7.30-7.40 (m, 3H), 7.92 (br a, 1H), 8.27 (br s, 1H)

AP-MS (m/z): 471 (M⁻−1)

Example 95 Compound 102

In a manner similar to that in Step 3 of Example 76, Compound 102 (64.6mg, 39%) was obtained from2-(methylsulfonylamino)acetophenone=thiosemicarbazone (100 mg, 0.333mmol) prepared in Step 2 of Example 88, isobutyryl chloride (140 μL,1.33 mmol) and pyridine (108 μL, 1.33 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.17 (d, J=6.9 Hz, 3H), 1.19 (d, J=6.9Hz, 3H), 1.25 (d, J=6.9 Hz, 6H), 1.29 (d, J=6.9 Hz, 6H), 3.05 (s, 3H),3.10-3.30 (m, 3H), 4.01 (dd, J=4.8, 14.2 Hz, 1H), 4.74 (dd, J=7.8, 14.2Hz, 1H), 5.37 (br s, 1H), 7.26-7.40 (m, 5H)

Example 96 Compound 103

Compound 102 (40.0 mg, 0.0805 mg) prepared in Example 95 was dissolvedin methanol (10 mL). To the solution was added potassium carbonate (1.00g, 7.24 mmol), and the mixture was vigorously stirred for 1 hour. Thereaction mixture was filtered, and the filtrate was concentrated. Then,to the residue was added chloroform, 1 mol/L hydrochloric acid andwater, and the mixture was extracted with chloroform. The organic layerwas washed with saturated aqueous sodium chloride, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by preparative thin layerchromatography (chloroform/methanol=20/1) to obtain Compound 103 (24.2mg, 84%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (d, J=6.9 Hz, 3H), 1.18 (d, J=6.9Hz, 3H), 1.21 (d, J=6.9 Hz, 3H), 1.23 (d, J=6.9 Hz, 3H), 2.50 (m, 1H),2.90 (s, 3H), 3.27 (m, 1H), 3.98 (dd, J=5.0, 13.9 Hz, 1H), 4.60 (dd,J=8.2, 13.9 Hz, 1H), 5.35 (br dd, J=5.0, 8.2 Hz, 1H), 7.26-7.40 (m, 5H),8.02 (br s, 1H)

Example 97 Compound 104

Step 1: In a manner similar to that in Step 1 of Example 1,3-(dimethylamino)propiophenone=thiosemicarbazone (491 mg, 46%) wasobtained from 3-(dimethylamino)propiophenone (910 mg, 4.26 mmol) andthiosemicarbazide (387 mg, 4.25 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound104 (116 mg, 33%) was obtained from3-(dimethylamino)propiophenone=thiosemicarbazone (210 mg, 0.839 mmol)prepared above, pivaloyl chloride (496 μL, 3.78 mmol) and pyridine (326μL, 3.78 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.31 (s, 9H), 2.23-2.29(m, 1H), 2.26 (br s, 3H), 2.27 (br s, 3H), 2.46 (ddd, J=8.8, 4.3, 11.3Hz, 1H), 2.87 (m, 1H), 3.31 (m, 1H), 7.20-7.36 (m, 5H), 7.90 (br s, 1H)

Example 98 Compound 105

Step 1: In a manner similar to that in Step 2 of Example 1,3-carbomethoxypropiophenone=thiosemicarbazone (10.6 g, 94%) was obtainedfrom 3-carbomethoxypropiophenone (8.13 g, 42.3 mmol) andthiosemicarbazide (3.86 g, 42.3 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound105 (9.70 g, 77%) was obtained from3-carbomethoxypropiophenone=thiosemicarbazone (7.76 g, 29.2 mmol)prepared above, pivaloyl chloride (14.4 mL, 117 mmol) and pyridine (11.3mL, 140 mmol).

1H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 2.37 (m,1H), 2.67 (m, 1H), 2.79 (m, 1H), 3.42 (m, 1H), 3.70 (s, 3H), 7.22-7.40(m, 5H), 7.89 (br s, 1H)

Example 99 Compound 106

Sodium hydroxide (2.7 g, 67 mmol) was dissolved in water (23 mL).Subsequently, to the solution was added methanol (30 mL) and thesolution was stirred. To the solution was added Compound 105 (9.65 g,22.3 mmol) prepared in Example 98, and the mixture was stirred at roomtemperature for 5 hours. To the reaction mixture was added 1 mol/Lhydrochloric acid (20 mL) and water (30 mL), and the deposited whitecrystals were collected by filtration. The resulting crystals werewashed with water and diisopropyl ether, and then, dried under reducedpressure to obtain Compound 106 (8.92 g, 96%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 1.33 (s, 9H), 2.00-2.51(br s, 1H), 2.44 (m, 1H), 2.66 (m, 1H), 2.88 (m, 1H), 3.44 (m, 1H),7.23-7.40 (m, 5H), 7.92 (br s, 1H)

Example 100 Compound 107

Compound 106 (1.21 g, 2.88 mmol) prepared in Example 99 was cooled to 0°C. Oxalyl chloride (5 mL) was added to the compound, and the solutionwas allowed to react at 0° C. for 1 hour. The solvent was evaporatedunder reduced pressure, and the residue was dried in vacuo. To theresidue was added tetrahydrofuran, and the mixture was stirred at 0° C.Then, to the reaction mixture was added 4 mol/L ammonia-methanolsolution (5 mL, 20 mmol), and the mixture was stirred at roomtemperature for 3 hours. To the reaction mixture was added 1 mol/Lhydrochloric acid (20 mL) and water (30 mL), and extracted withchloroform. The organic layer was washed with saturated aqueous sodiumchloride, and dried over anhydrous sodium sulfate. After the solvent wasevaporated under reduced pressure, to the resulting residue was addeddiisopropyl ether, and then the deposited white crystals were collectedby filtration. The resulting crystals were washed with water anddiisopropyl ether, and then dried under reduced pressure to obtainCompound 107 (8.92 g, 96%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.17 (s, 9H), 1.28 (s, 9H), 1.81-2.03(m, 1H), 2.15-2.30 (m, 1H), 2.49-2.75 (m,1H), 2.95-3.20 (m, 1H), 6.80(br s, 1H), 7.20-7.41 (m, 5H), 10.93 (br s, 2H)

Example 101 Compound 108

In a manner similar to that in Example 100, Compound 108 (65 mg, 60%)was obtained from Compound 106 (0.104 g, 0.248 mmol) prepared in Example99, oxalyl chloride (5 mL), hydroxylamine hydrochloride (0.017 g, 0.245mmol) and triethylamine (0.062 g, 0.614 mmol).

APCl-MS (m/z): 433 (M⁻−1)

Example 102 Compound 109

In a manner similar to that in Example 100, Compound 109 (1.08 g, 87%)was obtained from Compound 106 (1.20 g, 2.86 mmol) prepared in Example99, oxalyl chloride (5 mL) and 4 mol/L methylamine-methanol solution (10mL, 40 mmol).

AP-MS (m/z): 431 (M⁻−1)

Example 103 Compound 110

Step 1: In a manner similar to that in Step 1 of Example 1,3-(dimethylaminocarbonyl)propiophenone=thiosemicarbazone (3.67 g, 79%)was obtained from 3-(dimethylaminocarbonyl)propiophenone (4.00 g, 18.7mmol) and thiosemicarbazide (1.70 g, 18.7 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound110 (1.64 g, 49%) was obtained from3-(dimethylaminocarbonyl)propiophenone=thiosemicarbazone (2.00 g, 7.99mmol) prepared above, pivaloyl chloride (3.94 mL, 32.0 mmol) andpyridine (3.11 mL, 38.4 mmol).

AP-MS (m/z): 447 (M⁺+1)

Example 104 Compound 111

In a manner similar to that in Example 100, Compound 111 (480 mg, 84%)was obtained from Compound 106 (51.8 mg, 0.124 mmol) prepared in Example99, oxalyl chloride (0.5 mL), ethanolamine (7.58 mg, 0.248 mmol) andtriethylamine (18.8 mg, 0.186 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.33 (s, 9H), 2.16-2.25(m, 1H), 2.65-2.79 (m, 2H), 3.33-3.44 (m, 3H), 3.72 (m, 2H), 6.18 (br s,1H), 7.22-7.35 (m, 6H), 8.01 (br s, 1H)

Example 105 Compound 112

In a manner similar to that in Example 100, Compound 112 (400 mg, 68%)was obtained from Compound 106 (51.8 mg, 0.124 mmol) prepared in Example99, oxalyl chloride (0.5 mL), n-butylamine (18.14 mg, 0.248 mmol) andtriethylamine (18.8 mg, 0.186 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 0.92 (t, J=7.1 Hz, 3H), 1.25-1.60 (m,4H), 1.29 (s, 9H), 1.33 (s, 9H), 2.16 (m, 1H), 2.69 (m, 2H), 3.25 (m,2H), 3.67 (m, 1H), 5.62 (br s, 1H), 7.23-7.34 (m, 5H), 7.94 (br s, 1H)

Example 106 Compound 113

In a manner similar to that in Example 100, Compound 113 (50 mg, 81%)was obtained from Compound 106 (51.8 mg, 0.124 mmol) prepared in Example99, oxalyl chloride (0.5 mL), cyclohexylamine (24.6 mg, 0.248 mmol) andtriethylamine (18.8 mg, 0.186 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.05-1.50 (n, 6H), 1.28 (s, 9H), 1.33(s, 9H), 1.65-1.80 (m, 2H), 1.85-1.95 (m, 2H), 2.14 (m, 1H), 2.65 (m,2H), 3.37 (m, 1H), 3.38 (m, 1H), 5.50 (br s, 1H), 7.10-7.38 (m, 5H),7.93 (br s, 1H)

Example 107 Compound 114

Step 1: In a manner similar to that in Step 1 of Example 1,4-carbomethoxybutyrophenone=thiosemicarbazone (0.700 g, 88%) wasobtained from 4-carbomethoxybutyrophenone (0.588 g, 2.85 mmol) andthiosemicarbazide (0.260 g, 2.85 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound114 (318 mg, 64%) was obtained from4-carbomethoxybutyrophenone=thiosemicarbazone prepared above, pivaloylchloride (0.549 mL, 4.45 mmol) and pyridine (0.431 mL, 5.34 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.51-1.60(m, 1H), 2.10-2.30 (m, 2H), 2.44 (m, 2H), 3.03-3.17 (n, 1H), 3.68 (s,3H), 7.20-7.36 (m, 5H), 7.95 (br s, 1H)

Example 108 Compound 115

In a manner similar to that in Example 99, Compound 115 (234 mg, 95%)was obtained from Compound 114 (254 mg, 0.567 mmol) prepared in Example107, sodium hydroxide (70.0 mg, 1.75 mmol), water (2 mL) and ethanol (4mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.65-1.75(m, 1H), 2.10-2.35 (m, 2H), 2.50 (m, 2H), 3.10-3.20 (m, 1H), 7.23-7.35(m, 6H), 7.92 (br, s, 1H)

Example 109 Compound 116

In a manner similar to that in Example 100, Compound 116 (0.028 g, 55%)was obtained from Compound 115 (50.0 mg, 0.115 mmol) prepared in Example108, oxalyl chloride (0.5 mL) and 40% methylamine-methanol solution (5mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.50-1.65(m, ¹H), 2.21-2.35 (m, 4H), 2.80 (d, J=4.8 Hz, 3H), 3.13 (m, 1H), 5.71(br s, 1H) 7.20-7.35 (m, 5H), 7.97 (br s, 1H)

Example 110 Compound 117

In a manner similar to that in Example 100, Compound 117 (0.024 g, 47%)was obtained from Compound 115 (51.5 mg, 0.119 mmol) prepared in Example108, oxalyl chloride (0.5 mL) and 4 mol/L ammonia-methanol solution (5mL).

AP-MS (m/z): 431 (M⁻−1)

Example 111 Compound 118

In a manner similar to that in Step 3 of Example 76, Compound 118 (302mg, 26%) was obtained from2-(methylsulfonylamino)acetophenone=thiosemicarbazone (1.00 g, 3.49mmol) prepared in Step 2 of Example 88, acetic anhydride (659 μL, 6.98mmol) and pyridine (565 μL, 6.98 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.29 (s, 3H), 2.99 (s, 3H), 4.04 (d,J=14.0 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H), 7.30-7.41 (m, 5H)

AP-MS (m/z): 329 (M⁺+1)

Example 112 Compound 119

Compound 118 (10.6 mg, 0.0323 mmol) prepared in Example 111 wasdissolved in tetrahydrofuran (80 mL). To the solution was addeddimethylaminopyridine (7.9 mg, 0.0646 mmol) and pyridine (7.8 μL, 0.0969mmol), and the mixture was cooled to 0° C. To the solution was addedpivaloyl chloride (20 μL, 0.162 mmol), and the mixture was stirred at 0°C. for 5 minutes, and further Stirred at room temperature for 4 hours.To the reaction mixture was added water and 1 mol/L hydrochloric acid,and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layerchromatography (chloroform/methanol=12/1) to obtain Compound 119 (5.3mg, 40%).

¹H-NMR (270 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.32 (s, 3H), 2.95 (s,3H), 3.98 (dd, J=5.2, 14.0 Hz, 1H), 4.60 (dd, J=8.1, 13.9 Hz, 1H), 5.40(m, 1H), 7.29-7.40 (m, 5H), 8.11 (br s, 1H)

Example 113 Compound 120

2-(Methylsulfonylamino)acetophenone=thiosemicarbazone (300 mg, 1.05mmol) prepared in Step 2 of Example 88 was dissolved in tetrahydrofuran(18 mL). To the solution was added 4-dimethylaminopyridine (641 mg, 5.25mmol) and pivaloyl chloride (0.13 mL, 1.1 mmol), and the mixture wasstirred at room temperature. To the mixture was further added, after 1hour and after 2 hours each, pivaloyl chloride (0.065 mL, 0.53 mmol),and the mixture was stirred for 3.6 hours in total. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, and then dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bypreparative thin layer chromatography (chloroform/methanol=20/1) toobtain Compound 120 (88 mg, yield 22%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.96 (s, 3H), 4.06 (dd,J=6.2, 13.7 Hz, 1H), 4.19 (br s, 2H), 4.58 (dd, J=7.0, 13.7 Hz, 1H),5.20 (t, J=6.4 Hz, 1H), 7.27-7.55 (m, 5H)

AP-MS (m/z): 371 (M⁺+1)

Example 114 Compound 121

6-Bromohexanoic acid (469 mg, 2.41 mmol) was dissolved indichloromethane (15 mL). To the solution was added oxalyl chloride (0.28mL, 3.2 mmol), and the mixture was stirred at room temperature for 2hours. The solvent was evaporated from the reaction mixture underreduced pressure, and the resulting residue was dissolved indichloromethane (15 mL). To the solution was added Compound 120 (297 mg,0.802 mmol) prepared in Example 113 and pyridine (0.20 mL, 2.4 mmol),and the mixture was stirred at room temperature for 1 hour. After thereaction mixture was concentrated under reduced pressure, water wasadded to the residue, and the solution was extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by preparative thinlayer chromatography (chloroform/methanol=30/1) to obtain Compound 121(315 mg, yield 72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 1.50 (m, 2H), 1.67 (m,2H), 1.86 (q, J=6.7 Hz, 2H), 2.34 (t, J=7.3 Hz, 2H), 2.98 (s, 3H), 3.40(t, J=6.6 Hz, 2H), 3.99 (dd, J=5.2, 13.6 Hz, 1H), 4.63 (dd, J=8.2, 13.6Hz, 1H), 5.24 (dd, J=5.5, 7.9 Hz, 1H), 7.26-7.38 (m, 5H), 8.40 (br s,1H)

AP-MS (m/z): 547 (M⁺+1)

Example 115 Compound 122

Compound 121 (315 mg, 0.575 mmol) prepared in Example 114 was dissolvedin N,N-diethylformamide (9.5 mL). To the solution was added sodium azide(187 mg, 2.88 mmol), and the mixture was stirred at 80° C. for 2 hours.To the reaction mixture was added water and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, and then dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by preparative thin layer chromatography (hexane/ethylacetate=1/2) to obtain Compound 322 (211 mg, yield 72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 1.42 (m, 2H), 1.55-1.74(m, 4H), 2.35 (t, J=7.3 Hz, 2H), 2.97 (s, 3H), 3.28 (t, J=6.7 Hz, 2H),4.13 (dd, J=7.2, 14.3 Hz, 1H), 4.63 (dd, J=8.3, 13.5 Hz, 1H), 5.21 (dd,J=5.2, 8.0 Hz, 1H), 7.26-7.38 (m, 5H), 8.37 (s, 1H)

AP-MS (m/z): 510 (M⁺+1)

Example 116 Compound 123

Compound 122 (23.6 mg, 0.0463 mmol) prepared in Example 115 wasdissolved in tetrahydrofuran (1.0 mL). To the solution was addedtriphenylphosphine (36.4 mg, 0.139 mmol), and the mixture was stirred atroom temperature for 25 minutes. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous sodium chloride, and then driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by preparative -thin layerchromatography (chloroform/methanol/ammonia=5/0.8/0.2) to obtainCompound 123 (7.1 mg, yield 32%).

¹H-NMR (270 MHz, CDCl₃) δ (ppm): 1.31 (s, 9H), 1.47 (m, 2H), 1.57 (m,2H), 1.70 (m, 2H), 2.39 (m, 2H), 2.82 (m, 2H), 2.97 (s, 3H), 3.95 (d,J=13.7 Hz, 1H), 4.14 (br s, 3H), 4.65 (d, J=13.5 Hz, 1H), 7.24-7.35 (m,5H)

AP-MS (m/z): 484 (M⁺+1)

Example 117 Compound 124

Compound 123 (5.0 mg, 0.010 mmol) prepared in Example 116 was dissolvedin dichloromethane (0.4 mL). To the solution was added pyridine (0.0025mL, 0.031 mmol) and acetyl chloride (0.0015 mL, 0.021 mmol), and themixture was stirred at room temperature for 0.8 hour. To the reactionmixture was added water and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, and then dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bypreparative thin layer chromatography (chloroform/methanol=20/1) toobtain Compound 124 (3.9 mg, yield 72%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 1.37 (m, 2H), 1.53 (m,2H), 1.69 (m, 2H), 1.98 (s, 3H), 2.39 (t, J=7.4 Hz, 2H), 2.97 (s, 3H),3.24 (m, 2H), 3.98 (dd, J=5.2, 13.6 Hz, 1H), 4.64 (dd, J=8.2, 13.5 Hz,1H), 5.22 (dd, J=5.4, 8.2 Hz, 1H), 5.68 (m, 1H), 7.24-7.38 (m, 5H), 9.08(s, 1H)

FAB-MS (m/z): 526 (M⁺+1)

Example 118 Compound 125

Step 1: In a manner similar to that in Step 1 of Example 1,3′-hydroxyacetophenone=4-ethylthiosemicarbazone (342 mg, 70%) wasobtained from 3′-hydroxyacetophenone (279 mg, 2.05 mmol) and4-ethylthiosemicarbazide (242 mg, 2.03 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 125(90 mg, 60%) was obtained from3′-hydroxyacetophenone=4-ethylthiosemicarbazone (200 mg, 0.843 mmol)prepared above, acetic anhydride (260 mg, 2.53 mmol) and pyridine (108μL, 1.34 mmol).

¹11 NMR (270 MHz, CDCl₃) δ (ppm): 2.02 (s, 3H), 2.20 (s, 3H), 2.28 (s,3H), 2.30 (t, J=8.4 Hz, 3H), 2.36 (s, 3H), 3.30-3.47 (br s, 2H),7.20-7.40 (m, 5H)

Example 119 Compound 126

In a manner similar to that in Example 65, Compound 126 (81 mg, 49%) wasobtained from Compound 125 (187 mg, 0.515 mg) prepared in Example 118,methanol (10 mL) and potassium carbonate (1.00 g, 7.24 mmol)

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 2.23 (s,3H), 2.29 (t, J=8.4 Hz, 3H), 3.40 (br s, 2H), 6.65-6.80 (m, 3H), 7.13(m, 1H), 11.6 (br s, 1H)

Example 120 Compound 127

Compound 69 (50.5 mg, 0.172 mmol) prepared in Example 66 was dissolvedin dichloromethane (0.5 mL). To the solution was added triethylamine(17.4 mg, 0.172 mmol) and ethyl isocyanate (13.6 μL, 0.172 mmol), andthe mixture was stirred at room temperature for 12 hours. To thereaction mixture was added 1 mol/L hydrochloric acid and water, and themixture was subjected to separation. The organic layer was washed withsaturated aqueous sodium chloride and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by preparative thin layer chromatography(chloroform/methanol/water=90/10/1) to obtain Compound 127 (53.3 mg,85%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.21 (t, J=7.0 Hz, 3H), 2.09 (s, 3H),2.22 (s, 3H), 2.35 (s, 3H), 3.31 (n, 2H), 5.03 (br s, 1H), 7.06 (br d,J=8.4 Hz, 1H), 7.24-7.35 (m, 3H), 8.41 (br s, 1H)

Example 121 Compound 128

In a manner similar to that in Step 3 of Example 76, Compound 128 (500mg, 63%) was obtained from 3′-hydroxyacetophenone=thiosemicarbazone (398mg, 1.90 mmol) prepared in Step 1 of Example 59, isobutyryl chloride(1.56 mL, 7.60 mmol) and pyridine (721 mg, 9.12 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.09 (d, J=6.8 Hz, 3H), 1.10 (d, J=6.8Hz, 3H), 1.21 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.8 Hz, 3H), 1.29 (d, J=7.3Hz, 6H), 2.34 (s, 3H), 2.51 (m, 1H), 2.78 (m, 1H), 3.18 (m, 1H), 7.00(br d, J=7.3 Hz, 1H), 7.13 (br s, 1H), 7.25-7.33 (m, 2H), 7.93 (br s,1H)

Example 122 Compound 129

In a manner similar to that in Example 65, Compound 129 (298 mg, 85%)was obtained from Compound 128 (420 mg, 1.00 mmol) prepared in Example121 and potassium carbonate (1.00 g, 7.24 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.11 (d, J=7.0 Hz, 3H), 1.12 (d, J=7.0Hz, 3H), 1.22 (d, J=7.0 Hz, 3H), 1.23 (d, J=7.0 Hz, 3H), 2.23 (s, 3H),2.51 (m, 1H), 3.20 (m, 1H), 5.60 (br s, 1H), 6.63 (br d, J=7.3 Hz, 1H),6.85 (br s, 1H), 6.94 (br d, J=7.9 Hz, 1H), 7.15 (br t, J=7.9 Hz, 1H),8.00 (br s, 1H)

Example 123 Compound 130

In a manner similar to that in Step 3 of Example 76, Compound 130 (389mg, 88%) was obtained from 2′-chloroacetophenone=thiosemicarbazone (253mg, 1.11 mmol) prepared in Step 1 of Example 53, pivaloyl chloride (546μL, 4.44 mmol) and pyridine (389 μL, 4.80 mmol). ¹H NMR (270 MHz, CDCl₃)δ (ppm): 1.29 (s, 9H), 1.30 (s, 9H), 2.35 (s, 3H), 7.20-7.27 (m, 2H),7.35-7.43 (m, 2H), 7.95 (br s, 1H)

Example 124 Compound 131

In a manner similar to that in Step 3 of Example 76, Compound 131 (389mg, 86%) was obtained from 2′-chloroacetophenone=thiosemicarbazone (400mg, 1.89 mmol) prepared in Step 1 of Example 53, isobutyryl chloride(594 μL, 5.67 mmol) and pyridine (538 mg, 6.80 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.10 (d, J=6.6 Hz, 3H), 1.12 (d, J=6.6Hz, 3H), 1.23 (d, J=6.9 Hz, 2H), 1.25 (d, J=6.9 Hz, 3H), 2.39 (s, 3H),2.52 (m, 1H), 3.18 (m, 1H), 7.22-7.28 (m, 2H), 7.37-7.45 (m, 2H), 7.96(br s, 1H)

Example 125 Compound 132

Step 1: In a manner similar to that in Step 1 of Example 1,1-(5-bromo-2-thienyl)ethanone=thiosemicarbazone (7.33 mg, 86%) wasobtained from 1-(5-bromo-2-thienyl)ethanone (630 mg, 3.07 mmol) andthiosemicarbazide (281 mg, 3.07 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 132(158 mg, 58%) was obtained from1-(5-bromo-2-thienyl)ethanone=thiosemicarbazone (2.11 mg, 0.758 mmol)prepared above and acetic anhydride (10 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.15 (s, 3H), 2.19 (s, 3H), 2.36 (s,3H), 6.84 (br s, 1H), 6.86 (br s, 1H), 8.29 (br s, 1H)

Example 126 Compound 133

Step 1: In a manner similar to that in Step 1 of Example 1,1-(3-bromo-2-thienyl)ethanone=thiosemicarbazone was obtained from1-(3-bromo-2-thienyl)ethanone (108 mg, 0.388 mmol) and thiosemicarbazide(36.5 mg, 0.399 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 133(139 mg, 99%) was obtained from1-(3-bromo-2-thienyl)ethanone=thiosemicarbazone prepared above andacetic anhydride (10 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.04 (s, 3H), 2.14 (s, 3H), 2.23 (s,3H), 2.41 (s, 3H), 6.96 (br s, 1H), 7.17 (br s, 1H), 9.08 (br s, 1H)

Example 127 Compound 134

Step 1: In a manner similar to that in Step 1 of Example 1,1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone was obtained from1-(3-chloro-2-thienyl)ethanone (137 mg, 0.853 mmol) andthiosemicarbazide (78 mg, 0.853 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1, Compound 134(158 mg, 58%) was obtained from1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone prepared above andacetic anhydride (10 mL).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.14 (s, 3H), 2.21 (s, 3H), 2.43 (s,3H), 6.89 (d, J=5.3 Hz, 1H), 7.18 (d, J=5.3 Hz, 1H), 8.28 (br s, 1H)

Example 128 Compound 135

Step 1: In a manner similar to that in Step 1 of Example 1,1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone (96.1 mg, 71%) wasobtained from 1-(3-chloro-2-thienyl)ethanone (92.9 tag, 0.578 mmol) andthiosemicarbazide (52.9 mg, 0.578 mmol).

Step 2: In a manner similar to that in Step 3 of Example 76, Compound134 (90 mg, 60%) was obtained from1-(3-chloro-2-thienyl)ethanone=thiosemicarbazone (86.9 mg, 0.372 mmol)prepared above, pivaloyl chloride (138 μL, 1.12 mmol) and pyridine (108μL, 1.34 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.33 (s, 9H), 1.35 (s, 9H), 2.43 (s,3H), 6.90 (d, J=6.3 Hz, 1H), 7.20 (d, J=6.3 Hz, 1H), 7.97 (br s, 1H)

Example 129 Compound 136

Compound 14 (41 mg, 0.17 mmol) prepared in Example 11 was dissolved inacetonitrile (0.5 mL). To the solution was added di-tert-butyldicarbonate (0.114 mg, 0.522 mmol) and DMAP (43 mg, 0.35 mmol), and themixture was stirred at room temperature for 1 hour. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, and then dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bypreparative thin layer chromatography (chloroform/methanol=20/1) toobtain Compound 136 (24 mg, 41%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.47 (s, 9H), 2.21 (s, 3H), 2.40 (s,3H), 7.14-7.48 (m, 6H)

AP-MS (m/z): 334 (M⁻−1)

Example 130 Compound 137

Compound 14 (74 mg, 0.31 mmol) prepared in Example 11 was dissolved inN,N-dimethylformamide (2 mL). To the solution was added 60% sodiumhydride (50 mg, 1.3 mmol) and dimethylcarbamoyl chloride (0.116 mL, 1.26mmol), and the mixture was stirred at room temperature for 1 hour. Tothe reaction mixture was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, and then dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby preparative thin layer chromatography (chloroform/methanol=40/1, thenethyl acetate/n-hexane=3/1) to obtain Compound 137 (44 mg, 46%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.23 (s, 3H), 2.37 (s, 3H), 3.00 (s,6H), 7.20-7.45 (m, 5H)

AP-MS (m/z): 307 (M⁺+1)

Example 131 Compound 138

Step 1: Copper (II) bromide (130 mg, 0.583 mmol) was dissolved inacetonitrile (5.4 mL). To the solution was added 4A-butyl nitrite (0.093mL, 0.78 mmol) under ice cooling. After being stirred for 10 minutes, tothe mixture was added Compound 14 (180 mg, 0.486 mmol) prepared inExample 11, and the mixture was stirred for 1 hour with graduallyraising the temperature up to room temperature. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=1/18) to obtain3-acetyl-5-bromo-2-methyl-2-phenyl-1,3,4-thiadialine (145 mg, 84%).

Step 2: 3-Acetyl-5-bromo-2-methyl-2-phenyl-1,3,4-thiadialine (50 mg,0.17 mmol) prepared above was dissolved in dichloromethane (0.5 mL). Tothe solution was added piperidine (0.033 mL, 0.33 mmol), and the mixturewas stirred at room temperature for 20 minutes. To the reaction mixturewas further added piperidine (0.165 mL, 1.67 mmol), and the mixture wasstirred at the same temperature for 5.5 hours. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by preparative thinlayer chromatography (chloroform) to obtain Compound 138 (12 mg, 24%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.60 (m, 6H), 2.25 (s, 3H), 2.40 (s,3H), 3.24 (m, 4H), 7.20-7.39 (m, 3H), 7.45 (m, 2H)

AP-MS (m/z): 304 (M⁺+1)

Example 132 Compound 139

In a manner similar to that in Step 2 of Example 131, Compound 139 (38mg. 59%) was obtained from3-acetyl-5-bromo-2-methyl-2-phenyl-1,3,4-thiadiallyn (61 mg, 0.20 mmol)prepared in Step 1 of Example 131 and 4-methylpiperidine (0.483 mL, 4.08mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.96 (d, J=6.4 Hz, 3H), 1.25 (m, 2H),1.44-1.71 (m, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 2.88 (m, 2H), 3.61 (m,2H), 7.20-7.49 (m, 3H), 7.46 (m, 2H)

AP-MS (m/z): 318 (M⁺+1)

Example 133 Compound 140

Compound 118 (50 mg, 0.15 mmol) prepared in Example 111 was dissolved indichloromethane (2 mL). To the solution was added pyridine (0.031 mL,0.38 mmol) and hexanoyl chloride (0.053 mL, 0.38 mmol), and the mixturewas stirred at room temperature for 2.5 hours. To the reaction mixturewas further added pyridine (0.012 mL, 0.15 mmol) and hexanoyl chloride(0.021 mL, 0.15 mmol), and the mixture was stirred at the sametemperature for 1 hour. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride, and then dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by preparative thin layer chromatography(chloroform/methanol=15/1) to obtain Compound 140 (52 nag, 80%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 0.90 (t, J=6.6 Hz, 3H), 1.22-1.41 (m,4H), 1.64 (m, 2H), 2.31 (s, 3H), 2.32 (t, J=7.5 Hz, 2H), 2.96 (s, 3H),3.98 (dd, J=5.4, 13.9 Hz, 1H), 4.60 (dd, J=8.1, 13.9 Hz, 1H), 5.38 (dd,J=5.4, 8.1 Hz, 1H), 7.20-7.44 (m, 5H), 8.02 (s, 1H)

AP-MS (m/z): 427 (M⁺+1)

Example 134 Compound 141

In a manner similar to that in Example 133, Compound 141 (22 mg, 18%)was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example111, pyridine (0.062 mL, 0.78 mmol) and crotonoyl chloride (0.075 mL,0.78 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.91 (dd, J=1.7, 7.0 Hz, 3H), 2.32 (s,3H), 2.97 (s, 3H), 3.99 (dd, J=5.6, 13.9 Hz, 1H), 4.61 (dd, J=7.6, 13.9Hz, 1H), 5.51 (dd, J=5.6, 7.6 Hz, 1H), 5.86 (dd, J=1.7, 15.2 Hz, 1H),7.03 (dd, J=7.0, 15.2 Hz, 1H), 7.22-7.41 (m, 5H), 8.49 (s, 1H)

AP-MS (m/z): 397 (M⁺+1)

Example 135 Compound 142

In a manner similar to that in Example 133, Compound 142 (42 mg, 70%)was obtained from Compound 118 (50 mg, 0.15 mmol) prepared in Example111, pyridine (0.062 mL, 0.76 mmol) and cyclopropanecarbonyl chloride(0.070 mL, 0.76 mmol).

¹H NMR (270 MHz, CD₃OD) δ (ppm): 0.87-0.98 (m, 4H), 1.77 (m, 1H), 2.28(s, 3H), 3.01 (s, 3H), 3.97 (d, J=14.0 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H),7.22-7.42 (m, 5H)

AP-MS (m/z): 397 (M⁺+1)

Example 136 Compound 143

In a manner similar to that in Example 133, Compound 143 (24 mg, 22%)was obtained from Compound 118 (80 mg, 0.24 mmol) prepared in Example111, pyridine (0.069 mL, 0.85 mmol) and 2-acetoxyisobutyryl chloride(0.12 mL, 0.85 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.65 (s, 3H), 1.67 (s, 3H), 2.15 (s,3H), 2.32 (s, 3H), 2.97 (s, 3H), 3.99 (dd, J=5.5, 14.0 Hz, 1H), 4.61(dd, J=8.1, 14.0 Hz, 1H), 5.39 (dd, J=5.5, 8.1 Hz, 1H), 7.29-7.46 (m,5H), 8.53 (s, 1H)

AP-MS (m/z): 457 (M⁺+1)

Example 137 Compound 144

Compound 143 (21 mg, 0.045 mmol) prepared in Example 136 was dissolvedin a mixed solvent of methanol (1.6 mL) and water (0.8 mL). To thesolution was added lithium hydroxide (11 mg, 0.45 mmol), and the mixturewas stirred at room temperature for 3.5 hours. To the reaction mixturewas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by preparative thinlayer chromatography (chloroform/methanol=9/1) to obtain Compound 144(11 mg, 56%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.44 (s, 3H), 1.48 (s, 3H), 2.32 (s,3H), 2.85 (br s, 1H), 2.97 (s, 3H), 3.98 (dd, J=5.6, 13.9 Hz, 1H), 4.63(dd, J=7.8, 13.9 Hz, 1H), 5.53 (dd, J=5.6, 7.8 Hz, 1H), 7.25-7.42 (m,5H), 9.36 (s, 1H)

AP-MS (m/z): 415 (M⁺+1)

Example 138 Compound 145

In a manner similar to that in Example 133, Compound 145 (53 mg, 86%)was obtained from Compound 118 (50 mg, 0.15 mmol) prepared in Example111, pyridine (0.031 mL, 0.38 mmol) and methoxyacetyl chloride (0.035mL, 0.38 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.32 (s, 3H), 2.96 (s, 3H), 3.49 (s,3H), 4.00 (s, 2H), 4.00 (dd, J=5.8, 13.9 Hz, 1H), 4.61 (dd, J=7.8, 13.9Hz, 1H), 5.46 (dd, J=5.8, 7.8 Hz, 1H), 7.25-7.44 (m, 5H), 8.94 (s, 1H)

AP-MS (m/z): 401 (M⁺+1)

Example 139 Compound 146

In a manner similar to that in Example 133, Compound 146 (105 mg, 85%)was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example111, pyridine (0.062 mL, 0.76 mmol) and chloroacetyl chloride (0.061 mL,0.76 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.34 (s, 3H), 2.97 (s, 3H), 4.02 (dd,J=5.6, 14.0 Hz, 1H), 4.11 (d, J=15.9 Hz, 1H), 4.18 (d, J=15.9 Hz, 1H),4.62 (dd, J=7.8, 14.0 Hz, 1H), 5.28 (dd, J=5.6, 7.8 Hz, 1H), 7.22-7.43(m, 5H), 8.87 (s, 1H)

AP-MS (m/z): 405 (M⁺+1)

Example 140 Compound 147

Compound 146 (50 mg, 0.12 mmol) prepared in Example 139 was dissolved inmethanol (1 mL). To the solution was added 50% aqueous dimethylamine(0.033 and the mixture was stirred at room temperature for 1 hour. Tothe reaction mixture was further added 50% aqueous dimethylamine (0.033mL), and the mixture was stirred at the same temperature for 1.5 hours.To the reaction mixture was added water, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride, and then dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby preparative thin layer chromatography (chloroform/acetone=1/1) toobtain Compound 147 (20 mg, 39%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.34 (s, 3H), 2.38 (s, 6H), 2.96 (s,3H), 3.06 (d, J=17.3 Hz, 1H), 3.10 (d, J=17.3 Hz, 1H), 4.00 (d, J=13.9Hz, 1H), 4.61 (d, J=13.9 Hz, 1H), 5.36 (br, 1H), 7.25-7.41 (m, 5H)

AP-MS (m/z): 414 (M⁺+1)

Example 141 Compound 148

In a manner similar to that in Example 133, Compound 148 (304 mg, 74%)was obtained from Compound 118 (297 mg, 0.903 mmol) prepared in Example111, pyridine (0.183 mL, 2.26 mmol) and methyl 4-(chloroformyl)butyrate(0.312 mL, 2.26 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.00 (m, 2H), 2.32-2.56 (m, 4H), 2.34(s, 3H), 2.99 (s, 3H), 3.71 (s, 3H), 4.01 (dd, J=5.4, 13.9 Hz, 1H), 4.63(dd, J=7.9, 13.9 Hz, 1H), 5.45 (m, 1H), 7.21-7.49 (m, 5H), 8.54 (s, 1H)

AP-MS (m/z): 457 (M⁺+1)

Example 142 Compound 149

In a manner similar to that in Example 137, after Compound 148 (262 mg,0.573 mmol) prepared in Example 141 was treated with lithium hydroxidemonohydrate (206 mg, 4.91 mmol), to the reaction mixture was added iceand 0.5 mol/L hydrochloric acid, and the mixture was extracted with amixed solvent of chloroform and methanol. After the extract wasconcentrated, the residue was purified by silica gel columnchromatography (chloroform/methanol=43/7) to obtain Compound 149 (222mg, 88%).

¹H NMR (270 MHz, CD₃OD) δ (ppm): 1.89 (m, 2H), 2.28 (s, 3H), 2.33 (t,J=7.3 Hz, 2H), 2.43 (t, J=7.5 Hz, 2H), 3.01 (s, 3H), 3.99 (d, J=14.0 Hz,1H), 4.56 (d, J=14.0 Hz, 1H), 7.20-7.45 (m, 5H)

AP-MS (m/z): 441 (M⁻−1)

Example 143 Compound 150

Compound 149 (83 mg, 0.19 mmol) prepared in Example 142 was dissolved in1,2-dichloroethane (3.2 mL). To the solution was added thionyl chloride(3.2 mL), and the mixture was stirred at 60° C. for 2.5 hours. Thereaction mixture was concentrated under reduced pressure, and then theresidue was purified by preparative thin layer chromatography(chloroform/methanol=20/1) to obtain Compound 150 (61 mg, 76%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.09 (m, 2H), 2.29 (s, 3H), 2.80 (t,J=6.5 Hz, 4H), 3.05 (s, 3H), 3.95 (dd, J=3.7, 13.9 Hz, 1H), 4.82 (dd,J=9.6, 13.9 Hz, 1H), 5.70 (dd, J=3.7, 9.6 Hz, 1H), 7.29-7.47 (m, 3H),7.58 (m, 2H)

AP-MS (m/z): 425 (M⁺+1)

Example 144 Compound 151

In a manner similar to that in Example 133, Compound 151 (113 mg, 78%)was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example111, pyridine (0.062 mL, 0.76 mmol) and 4-bromobutyryl chloride (0.088mL, 0.76 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.20 (m, 2H), 2.31 (s, 3H), 2.55 (t,J=6.9 Hz, 2H), 2.96 (s, 3H), 3.47 (t, J=6.2 Hz, 2H), 3.99 (dd, J=5.5,13.9 Hz, 1H), 4.61 (dd, J=7.9, 13.9 Hz, 1H), 5.37 (dd, J=5.5, 7.9 Hz,1H), 7.23-7.42 (m, 5H), 8.18 (s, 1H)

AP-MS (m/z): 476 (M⁻−1)

Example 145 Compound 152

Compound 151 (70 mg, 0.15 mmol) prepared in Example 144 was dissolved inN,N-dimethylformamide (1.8 mL). To the solution was added 60% sodiumhydride (9 Mg, 0.2 mmol), and the mixture was stirred at roomtemperature for 2 hours. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, and then dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layerchromatography (chloroform/methanol=9/1) to obtain Compound 152 (51 mg,88%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.20 (m, 2H), 2.35 (s, 3H), 2.57 (m,2H), 2.95 (s, 3H), 3.93 (m, 2H), 3.99 (dd, J=5.5, 13.9 Hz, 1H), 4.61(dd, J=8.1, 13.9 Hz, 1H), 5.33 (dd, J=5.5, 8.1 Hz, 1H), 7.25-7.44 (m,5H)

AP-MS (m/z): 397 (M⁺+1)

Example 146 Compound 153

In a manner similar to that in Example 133, Compound 153 (120 mg, 80%)was obtained from Compound 118 (100 mg, 0.305 mmol) prepared in Example111, pyridine (0.087 mL, 1.1 mmol) and 5-bromovaleryl chloride (0.143mL, 1.07 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.75-1.98 (m, 4H), 2.31 (s, 3H), 2.36(t, 7.0 Hz, 2H), 2.96 (s, 3H), 3.40 (t, J=6.2 Hz, 2H), 3.99 (dd, J=5.5,13.9 Hz, 1H), 4.61 (dd, J=7.9, 13.9 Hz, 1H), 5.40 (dd, J=5.5, 7.9 Hz,1H), 7.23-7.42 (m, 5H), 8.22 (s, 1H)

AP-MS (m/z): 491, 493 (M⁺+1)

Example 147 Compound 154

In a manner similar to that in Example 145, Compound 154 (36 mg, 72%)was obtained from Compound 153 (60 mg, 0.12 mmol) prepared in Example146 and 60% sodium hydride (7 mg, 0.2 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.81-2.02 (m, 4H), 2.36 (s, 3H), 2.54(m, 2H), 2.94 (s, 3H), 3.85 (m, 2H), 3.95 (dd, J=4.8, 13.8 Hz, 1H), 4.56(dd, J=8.4, 13.8 Hz, 1H), 5.41 (dd, J=4.8, 8.4 Hz, 1H), 7.25-7.41 (m,5H)

AP-MS (m/z): 411 (M⁺+1).

Example 148 Compound 155

In a manner similar to that in Example 133, Compound 155 (122 mg, 80%)was obtained from Compound 118 (99 mg, 0.30 mmol) prepared in Example111, pyridine (0.061 mL, 0.75 mmol) and 6-bromohexanoyl chloride (0.115mL, 0.754 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.40-1.77 (m, 4H), 1.87 (m, 2H), 2.31(s, 3H), 2.35 (t, J=7.4 Hz, 2H), 2.96 (s, 3H), 3.40 (t, J=6.6 Hz, 2H),3.99 (dd, J=5.4, 14.0 Hz, 1H), 4.60 (dd, J=7.9, 14.0 Hz, 1H), 5.36 (dd,J=5.4, 7.9 Hz, 1H), 7.20-7.43 (m, 5H), 8.06 (s, 1H)

AP-MS (m/z): 505, 507 (M⁺+1)

Example 149 Compound 156

In a manner similar to that in Example 145, Compound 156 (17 mg, 32%)was obtained from Compound 155 (63 mg, 0.12 mmol) prepared in Example148 and 60% sodium hydride (7 mg, 0.2 mmol).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 1.55-1.78 (m, 6H), 2.19 (s, 3H), 2.68(m, 2H), 2.95 (s, 3H), 3.87 (dd, J=7.9, 13.7 Hz, 1H), 4.12 (m, 2H), 4.29(dd, J=5.6, 13.7 Hz, 1H), 7.20-7.41 (m, 6H)

AP-MS (m/z): 425 (M⁺+1)

Example 150 Compound 157

Compound 99 (1.50 g, 3.21 mmol) prepared in Example 92 was dissolved inmethanol (30 mL). To the solution was gradually added sodium borohydride(1.21 g, 32.0 mmol) at 50° C., and the mixture was stirred at the sametemperature for 1.5 hours. To the reaction mixture was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, and then dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/methanol=20/1) to obtain Compound 157 (0.26 g, 21%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.31 (s, 9H), 2.62 (m, 1H), 2.94 (s,3H), 3.22 (m, 1H), 3.41 (m, 1H), 3.61 (m, 1H), 4.21 (s, 2H), 4.79 (m,1H), 7.19-7.38 (m, 5H)

AP-MS (m/z): 385 (M⁺+1)

Example 151 Compound 158

In a manner similar to that in Example 133, Compound 158 (114 mg, 85%)was obtained from Compound 157 (97 mg, 0.25 mmol) prepared in Example150, pyridine (0.051 mL, 0.63 mmol) and 4-bromobutyryl chloride (0.073mL, 0.63 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.32 (s, 9H), 2.22 (m, 2H), 2.58 (t,J=7.4 Hz, 2H) 2.65 (m, 1H), 2.97 (s, 3H), 3.27 (m, 1H), 3.39 (m, 1H),3.49 (t, J=6.2 Hz, 2H), 3.62 (m, 1H), 4.45 (br t, 1H), 7.21-7.39 (m,5H), 8.00 (s, 1H)

AP-MS (m/z): 533, 535 (M⁺+1)

Example 152 Compound 159

In a manner similar to that in Example 145, Compound 159 (64 mg, 68%)was obtained from Compound 158 (110 mg, 0.206 mmol) prepared in Example151 and 60% sodium hydride (12 mg, 0.31 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.23 (n, 2H), 2.56 (m,2H), 2.61 (m, 1H), 2.97 (s, 3H), 3.27 (m, 1H), 3.40 (m, 1H), 3.63 (m,1H), 3.98 (m, 2H), 4.01 (br t, J=3.5 Hz, 1H), 7.20-7.37 (m, 5H)

AP-MS (m/z): 453 (M⁺+1)

Example 153 Compound 160

Compound 119 (21 mg, 0.052 mmol) prepared in Example 112 was dissolvedin a mixed solvent of toluene (1 mL) and tetrahydrofuran (1 mL). To thesolution was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide(Lawesson's reagent) (43 mg, 0.11 mmol), and the mixture was stirred at90° C. for 5 hours. The reaction mixture was purified by preparativethin layer chromatography (chloroform/methanol=20/1) to obtain Compound160 (15 mg, 67%).

¹NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 2.76 (s, 3H), 3.08 (s, 3H),4.08 (dd, J=7.3, 13.8 Hz, 1H), 5.03 (t, J=7.3 Hz, 1H), 5.54 (dd, J=7.3,13.8 Hz, 1H), 7.26-7.42 (m, 5H), 8.16 (s, 1H)

AP-MS (m/z): 429 (M⁺+1)

Example 154 Compound 161

In a manner similar to that in Example 100, Compound 161 (70 mg, 37%)was obtained from Compound 106 (0.165 g, 0.393 mmol) prepared in Example99, oxalyl chloride (2 mL), 2-(methylamino)ethanol (295 mg, 3.93 mmol)and triethylamine (476 mg, 4.72 mmol).

AP-MS (m/z): 475 (M⁻−1)

Example 155 Compound 162

In a manner similar to that in Example 100, Compound 162 (135 mg, 68%)was obtained from Compound 106 (0.165 g, 0.393 mmol) prepared in Example99, oxalyl chloride (2 mL) and diethanolamine (413 mg, 3.93 mmol).

AP-MS (m/z): 507 (M⁺+1)

Example 156 Compounds 163 and 164

In a manner similar to that in Example 100, Compound 163 (6.2 mg, 5%)and Compound 164 (36.1 mg, 31%) were obtained from Compound 106 (0.099g, 0.237 mmol) prepared in Example 99, oxalyl chloride (1.25 mL) and3-amino-1,2-propanediol (92 μL, 1.19 mmol).

Compound 163

AP-MS (m/z): 493 (M⁺+1)

Compound 164

AP-MS (m/z): 493 (M⁺+1)

Example 157 Compound 165

In a manner similar to that in Example 100, Compound 165 (37 mg, 33%)was obtained from Compound 115 (0.102 g, 0.236 mmol) prepared in Example108, oxalyl chloride (1.25 mL) and 2-aminoethanol (144 mg, 2.36 mmol).

AP-MS (m/z): 477 (M⁺+1)

Example 158 Compound 166

Compound 105 (0.200 g, 0.461 mmol) prepared in Example 98 was dissolvedin tetrahydrofuran (2 mL). To the solution was added lithium aluminiumhydride (30 mg, 0.791 mmol) at 0° C., and the mixture was stirred atroom temperature for 2 hours. To the reaction mixture was added waterand 30% aqueous sodium hydroxide. The insoluble precipitate was removedby filtration, and the filtrate was concentrated under reduced pressure.The residue was purified by preparative thin layer chromatography(chloroform/methanol=9/1) to obtain Compound 166 (64.0 mg, 34%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.32 (s, 9H), 1.65 (m,1H), 2.08 (m, 1H), 2.33 (m, 1H), 3.16 (m, 1H), 3.78 (m, 2H), 7.21-7.38(m, 5H), 7.95 (br s, 1H)

AP-MS (m/z): 404 (M⁻−1)

Example 159 Compound 167

Compound 166 (0.0448 g, 0.110 mmol) prepared in Example 158 wasdissolved in N,N-dimethylacetamide (0.5 mL). To the solution was addedsulfamoyl chloride (51.1 mg, 0.442 mmol) at 0° C. with stirring, and themixture was stirred at 0° C. for 20 minutes. After to the reactionmixture was added water, and the mixture was stirred. The depositedsolid was collected by filtration, and dried under reduced pressure. Theresulting solid was purified by preparative thin layer chromatography(chloroform/methanol=30/1) to obtain Compound 167 (30.2 mg, 57%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.33 (s, 9H), 1.89 (m,1H), 2.14 (n, 1H), 2.38 (m, 1H), 3.32 (m, 1H), 4.28 (m, 1H), 4.43 (m,1H), 5.08 (br s, 1H), 7.29 (m, 5H), 7.93 (br s, 1H)

AP-MS (m/z): 483 (M⁻−1)

Example 160 Compounds 168 and 169

Step 1: 2-Aminoacetophenone hydrochloride (4.56 g, 26.6 mmol) wasdissolved in dichloromethane (250 mL). To the solution was addedtriethylamine (9.30 mL, 66.7 mmol), and the mixture was stirred at roomtemperature for 10 minutes. After the reaction mixture was cooled to 0°C., chloromethanesulfonyl chloride (purity 90%, 3.60 mL, 36.3 mmol) wasadded to the mixture, and the mixture was stirred at the sametemperature for 1 hour. To the reaction mixture was added 2 mol/Lhydrochloric acid, and the mixture was extracted with chloroform. Theorganic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. To the residue was added diethyl ether, and thedeposited crystals were collected by filtration, and dried to obtain2-(chloromethylsulfonylamino)acetophenone (5.00 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 4.67 (s, 2H), 4.94 (s, 2H), 7.54 (t,J=8.1 Hz, 2H), 7.67 (t, J=7.5 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 8.01 (brs, 1H)

AP-MS (m/z): 247 (M⁺)

Step 2: 2-(Chloromethylsulfonylamino)acetophenone (1.00 g, 4.05 mmol)prepared above and thiosemicarbazide hydrochloride (1.03 g, 8.07 mmol)were dissolved in methanol (60 mL). To the solution was addedconcentrated hydrochloric acid (1.00 mL), and the mixture was stirred at60° C. for 2 hours. The reaction mixture was concentrated, and to theresidue was added ethyl acetate and saturated aqueous sodiumhydrogencarbonate, and the mixture was subjected to separation. Theorganic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=1/1 and 2/1) to obtain

2-(chloromethylsulfonylamino)acetophenone=thiosemicarbazone (0.51 g,40%).

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 4.17 (s, 2H), 4.93 (s, 2H), 7.37-7.42(m, 3H), 7.52-7.56 (m, 2H), 8.13 (br s, 1H), 8.48 (br, 2H), 8.85 (br s,1H)

AP-MS (m/z): 319 (M⁺)

Step 3: g-(Chloromethylsulfonylamino)acetophenone=thiosemicarbazone(7.48 g, 23.4 mmol) prepared above was dissolved in chloroform (250 mL).To the solution was added pyridine (11.4 mL, 141 mmol) and pivaloylchloride (8.70 mL, 70.6 mmol), and the mixture was stirred at roomtemperature for 30 minutes. To the reaction mixture was added aceticanhydride (4.40 mL, 46.6 mmol), and the mixture was further stirred atroom temperature for 15 hours. To the reaction mixture was added 2 mol/Lhydrochloric acid, and the mixture was extracted with chloroform. Theorganic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=1/1 and 2/1) to obtain Compound168 (3.56 g, 25%) and Compound 169 (1.77 g, 14%).

Compound 168

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 1.16 (s, 9H), 2.23 (s, 3H), 4.00 (dd,J=11.3, 8.0 Hz, 1H), 4.47 (dd, J=11.3, 2.5 Hz, 1H), 4.91 (d, J=12.0 Hz,1H), 4.97 (d, J=12.0 Hz, 1H), 7.28-7.39 (m, 5H), 8.10 (br s, 1H), 11.2(br s, 1H)

AP-MS (m/z): 446 (M⁺)

Compound 169

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.01 (s, 3H), 2.18 (s, 3H), 3.95 (d,J=14.3 Hz, 1H), 4.45 (d, J=14.3 Hz, 1H), 4.91 (d, J=12.0 Hz, 1H), 4.97(d, J=12.0 Hz, 1H), 7.25-7.39 (m, 5H), 8.08 (br s, 1H), 11.6 (br s, 1H)

AP-MS (m/z): 404 (M⁺)

Example 161 Compounds 170 and 171

Step 1: 2-Aminoacetophenone hydrochloride (1.00 g, 5.85 mmol) wasdissolved in dichloromethane (50 mL). To the solution was addedtriethylamine (2.50 mL, 17.9 mmol), and the mixture was stirred at roomtemperature for 10 minutes. After the reaction mixture was cooled to 0°C., chloroethanesulfonyl chloride (0.92 mL, 8.80 mmol) was added to themixture, and the mixture was stirred at the same temperature for 15minutes. To the reaction mixture was added 2 mol/L hydrochloric acid andthe mixture was extracted with chloroform. The organic layer was washedwith saturated aqueous sodium chloride, and then dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.To the residue was added a mixed solvent of ethyl acetate and n-hexanefor crystallization to obtain 2-(vinylsulfonylamino)acetophenone (0.42g, 32%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 4.54 (d, J=4.5 Hz, 2H), 5.42 (br s,1H), 5.94 (d, J=9.9 Hz, 1H), 6.28 (d, J=16.5 Hz, 1H), 6.53 (br dd,J=16.2, 9.9 Hz, 1H), 7.52 (t, J=7.5 Hz, 3H), 7.65 (t, J=7.8 Hz, 1H),7.93 (t, J=5.1 Hz, 1H)

AP-MS (m/z): 225 (M⁺)

Step 2: 2-(Vinylsulfonylamino)acetophenone (0.32 g, 1.42 mmol) preparedabove and thiosemicarbazide hydrochloride (0.27 g, 2.13 mmol) weredissolved in methanol (20 mL). To the solution was added concentratedhydrochloric acid (2 drops), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated. To theresidue was added ethyl acetate and saturated aqueous sodiumhydrogencarbonate, and the mixture was subjected to separation. Theorganic layer was washed with saturated aqueous sodium chloride, andthen dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane=1/1) to obtain2-(vinylsulfonylamino)acetophenone=thiosemicarbazone (0.25 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 4.10 (s, 2H), 5.97 (d, J=9.9 Hz, 1H),6.25 (d, J=16.8 Hz, 1H), 6.54 (dd, J=16.8, 9.9 Hz, 1H), 7.24-4.27 (m,2H), 7.42 (br s, 1H), 7.52-7.53 (m, 3H), 7.81 (br s, 1H), 8.70 (m, 1H)

AP-MS (m/z): 297 (M⁺)

Step 3: 2-(Vinylsulfonylamino)acetophenone=thiosemicarbazone (0.25 g,0.83 mmol) prepared above was dissolved in acetone (10 mL). To thesolution was added pyridine (0.34 mL, 4.17 mmol) and pivaloyl chloride(0.31 mL, 2.50 mmol), and the mixture was stirred at room temperaturefor 30 minutes. To the reaction mixture was added acetic anhydride (0.16mL, 1.66 mmol), and the mixture was further stirred for 3 days at roomtemperature. The reaction mixture was concentrated, and to the residuewas added ethyl acetate and 2 mol/L hydrochloric acid, and the mixturewas subjected to separation. The organic layer was washed with saturatedaqueous sodium chloride, and then dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethylacetate/n-hexane=1/1) to obtain Compound 170 (0.18 g, 52%) and Compound171 (0.10 g, 26%).

Compound 170

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.31 (s, 3H), 3.87 (dd,J=13.4, 5.0 Hz, 1H), 4.45 (dd, J=13.4, 7.9 Hz, 1H), 5.57 (br s, 1H),5.92 (d, J=9.9 Hz, 1H), 6.25 (d, J=16.5 Hz, 1H), 6.49 (dd, J=16.5, 9.9Hz, 1H), 7.27-7.34 (m, 5H), 8.22 (br s, 1H)

AP-MS (m/z): 424 (M⁺)

Compound 171

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.29 (s, 9H), 1.33 (s, 9H), 3.85 (dd,J=13.5, 4.8 Hz, 1H), 4.49 (dd, J=13.5, 8.1 Hz, 1H), 5.29 (br s, 1H),5.93 (br d, J=9.9 Hz, 1H), 6.27 (br d, J=16.5 Hz, 1H), 6.53 (br dd,J=16.4, 9.6 Hz, 1H), 7.27-7.34 (m, 5H), 8.06 (br s, 1H)

AP-MS (m/z): 466 (M⁺)

Example 162 Compound 172

Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 of Example 161 wasdissolved in acetonitrile (3 mL). To the solution was added morpholine(0.10 mL), and the mixture was stirred at 80° C. for 2 hours. Thereaction mixture was concentrated, and the residue was purified bysilica gel column chromatography (chloroform/methanol=10/1) to obtainCompound 172 (0.04 g, 77%).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.27 (s, 9H), 2.33 (s, 3H), 2.42-2.45(m, 4H), 2.78 (dquin, J=16.5, 6.0 Hz, 2H), 3.19 (t, J=6.6 Hz, 2H),3.65-3.68 (m, 4H), 4.04 (dd, J=14.1, 4.8 Hz, 1H), 4.55 (dd, J=14.1, 7.5Hz, 1H), 5.73 (br s, 1H), 7.30-7.38 (m, 5H), 8.05 (br s, 1H)

AP-MS (m/z): 511 (M⁺)

Example 163 Compound 173

In a manner similar to that in Example 162, Compound 173 (0.03 g, 66%)was obtained from Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 ofExample 161 and 70% aqueous ethylamine (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.10 (t, J=6.9 Hz, 3H), 1.27 (s, 9H),2.32 (s, 3H), 2.65 (quin, J=7.2 Hz, 2H), 3.05-3.09 (m, 2H), 3.18-3.20(m, 2H), 4.00 (d, J=13.5 Hz, 1H), 4.55 (d, J=13.8 Hz, 1H), 7.30-7.37 (m,5H), 8.07 (br s, 1H)

AP-MS (m/z): 470 (M⁺+1)

Example 164 Compound 174

In a manner similar to that in Example 162, Compound 174 (0.03 g, 67%)was obtained from Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 ofExample 161 and 2 mol/L dimethylamine methanol solution (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.26 (s, 9H), 2.24 (s, 6H), 2.31 (s,3H), 2.71-2.31 (m, 2H), 3.12-3.19 (m, 2H), 4.00 (d, J=13.5 Hz, 1H), 4.56(d, J=13.5 Hz, 1H), 6.00 (br s, 1H), 7.31-7.36 (m, 5H), 8.06 (br s, 1H)

AP-MS (m/z): 469 (M⁺)

Example 165 Compound 175

In a manner similar to that in Example 162, Compound 175 (0.03 g, 52%)was obtained from Compound 170 (0.05 g, 0.11 mmol) prepared in Step 3 ofExample 161 and 2-aminoethanol (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 126 (s, 9H), 2.35 (s, 3H), 2.65-2.78(m, 2H), 3.08-3.30 (m, 4H), 3.64 (t, J=5.1 Hz, 2H), 3.98 (d, J=13.5 Hz,1H), 4.54 (d, J=13.5 Hz, 1H), 7.26-7.38 (m, 5H), 8.25 (br s, 1H)

AP-MS (m/z): 485 (M⁺)

Example 166 Compound 176

In a manner similar to that in Example 162, Compound 176 (0.01 g, 26%)was obtained from Compound 171 (0.05 g, 0.11 mmol) prepared in Step 3 ofExample 161 and 70% aqueous ethylamine (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.18 (m, 3H), 1.28 (s, 9H), 1.34 (s,9H), 2.63 (quin, J=7.0 Hz, 2H), 2.73 (br q, J=6.3 Hz, 1H), 2.84 (br q,J=6.2 Hz, 1H), 3.18 (br t, J=6.6 Hz, 2H), 4.02 (d, J=13.2 Hz, 1H), 4.58(d, J=13.2 Hz, 1H), 5.85 (br s, 1H), 7.27-7.35 (m, 5H), 8.02 (br s, 1H)

AP-MS (m/z): 512 (M⁺+1)

Example 167 Compound 177

In a manner similar to that in Example 162, Compound 177 (0.02 g, 39%)was obtained from Compound 171 (0.05 g, 0.11 mmol) prepared in Step 3 ofExample 161 and 2 mol/L dimethylamine methanol solution (0.10 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.28 (s, 9H), 1.34 (s, 9H), 2.25 (s,6H), 2.73 (br q, J=6.3 Hz, 1H), 2.84 (br q, J=6.2 Hz, 1H), 3.18 (br t,J=6.6 Hz, 2H), 4.02 (d, J=13.2 Hz, 1H), 4.58 (d, J=13.2 Hz, 1H), 5.85(br s, 1H), 7.27-7.35 (m, 5H), 8.02 (br s, 1H)

AP-MS (m/z): 512 (M⁺+1)

Example 168 Compound 178

In a manner similar to that in Example 11, Compound 178 (64.0 mg, 38%)was obtained from carbomethoxypropiophenone=thiosemicarbazone (0.144 g,0.543 mol) prepared in Step 1 of Example 98, acetic anhydride (77 μL,0.814 mmol) and pyridine (79 μL, 0.977 mmol).

¹H NMR (270 MHz,CDCl₃) δ (ppm): 2.13 (s, 3H), 2.20-2.70 (m, 4H), 3.61(s, 3H), 6.52 (br s, 2H), 7.20-7.35 (m, 5H)

Example 169 Compound 179

In a manner similar to that in Example 15, Compound 179 (24.0 mg, 94%)was obtained from Compound 178 (0.0200 g, 0.0650 mol) prepared inExample 168, pivaloyl chloride (16 μL, 0.130 mmol) and pyridine (15 μL,0.182 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 2.10 (s, 3H), 2.17-2.75(m, 4H), 3.57 (s, 3H), 7.18-7.32 (m, 5H), 8.02 (br s, 1H)

AP-MS (m/z): 390 (M⁻−1)

Example 170 Compound 180

Compound 100 (304 mg, 0.0690 mmol) prepared in Example 93 and ceriumchloride heptahydrate (257 mg, 0.690 mmol) were dissolved in methanol(800 mL). To the solution was gradually added sodium borohydride (522mg, 13.8 mmol), and the mixture was stirred at room temperature for 20minutes. The reaction mixture was concentrated under reduced pressure.To the residue was added 1 mol/L hydrochloric acid (100 mL), and themixture was extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform/acetone/ethyl acetate/n-hexane=9/1/1/1) to obtain Compound180 (217 mg, 85%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.14 (t, J=7.0 Hz, 6H), 2.68 (m, 1H),2.98 (s, 3H), 3.27 (m, 2H), 3.44 (m, 1H), 3.63 (m, 1H), 4.18 (br s, 2H),4.51 (br s, 1H), 7.30 (m, 5H)

AP-MS (m/z): 371 (M⁺+1)

Example 171 Compound 181

In a manner similar to that in Example 15, Compound 181 (87.3 mg, 71%)was obtained from Compound 180 (100 mg, 0.270 mmol) prepared in Example170, pyridine (65.4 μL, 0.810 mmol) and pivaloyl chloride (83.4 μL,0.676 mmol).

AP-MS (m/z): 455 (M⁺+1)

Example 172 Compound 182

Compound 180 (60.6 mg, 0.170 mmol) obtained in Example 170 was dissolvedin dichloromethane. To the solution was added pyridine (63.2 μL, 0.788mmol) and 5-bromovaleryl chloride (23.0 μL, 0.172 mmol), and the mixturewas stirred at room temperature for 5 hours. To the reaction mixture wasadded 1 mol/L hydrochloric acid and the mixture was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue wasdissolved in dimethyl sulfoxide (0.3 mL). To the solution was addedsodium acetate (58.7 mg), and the mixture was stirred at 100° C. for 5minutes. To the reaction mixture was added water (20 mL) and 1 mol/Lhydrochloric acid (20 mL), and the mixture was extracted withchloroform. And then, the organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by preparative thin layer chromatography,(chloroform/acetone/ethyl acetate/n-hexane=9/1/1/1) to obtain Compound182 (42.5 mg, 45%).

AP-MS (m/z): 453 (M⁺+1)

Example 173 Compound 183

Compound 180 (100 mg, 0.270 mmol) prepared in Example 170 and pyridine(31.5 μL, 0.389 mmol) were dissolved in dichloromethane (2 mL). To thesolution was added 4-bromobutyryl chloride (37.5 μL, 0.324 mmol) at 0°C., and the mixture was stirred at room temperature for 5 hours. To thereaction mixture was added 1 mol/L hydrochloric acid, and the mixturewas extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. To the residue was added methanol (20 mL) and potassiumcarbonate (1.0 g), and the mixture was vigorously stirred at roomtemperature for 20 minutes. To the reaction mixture was added water and1 mol/L hydrochloric acid, and the mixture was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,and the solvent was evaporated. The residue was purified by silica gelcolumn chromatography (chloroform/acetone/ethylacetate/n-hexane=9/1/1/1) to obtain Compound 183 (27.6 mg, 37%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.15 (d, J=6.6 Hz, 6H), 2.22 (m, 2H),2.55-2.67 (m, 3H), 2.94 (s, 3H), 3.31-3.47 (m, 3H), 3.61 (m, 1H),3.91-3.98 (m, 2H), 5.0 (br s, 1H), 7.20-7.35 (m, 5H)

AP-MS (m/z): 437 (M⁻−1)

Example 174 Compound 184

In a manner similar to that in Example 173, Compound 180 (84.1 mg, 0.227mmol) prepared in Example 170 was treated with pyridine (88.0 μL, 1.09mmol) and 5-bromovaleryl chloride (121 μL, 0.908 mmol), and then treatedwith methanol and potassium carbonate (1.0 g) to obtain Compound 184(89.1 mg, 81%).

AP-MS (m/z): 485 (M⁺+1)

Example 175 Compound 185

In a manner similar to that in Step 3 of Example 92, Compound 185 (16.7g, 85%) was obtained from3-(methylaulfortylaraino)propiophenone=thiosemicarbazone (14.4 g, 47.9mmol), propionyl chloride (16.7 mL, 192 mmol) and pyridine (18.6 mL, 230mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.12 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.3Hz, 3H), 2.37 (m, 2H), 2.63 (m, 3H), 2.96 (s, 3H), 3.35 (m, 2H), 3.58(m, 1H), 4.55 (br s, 1H), 7.20-7.35 (m, 5H), 8.01 (br s, 1H)

Example 176 Compound 186

In a manner similar to that in Example 170, Compound 186 (11.7 g, 81%)was obtained from Compound 185 (16.7 g, 40.5 mmol) prepared in Example175, cerium chloride heptahydrate (15.1 g, 40.5 mol) and sodiumborohydride (12.8 g, 338 mol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=8.7 Hz, 3H), 2.61-2.71 (m,3H), 2.97 (s, 3H), 3.27-3.47 (m, 2H), 3.60-3.67 (m, 1H), 4.21 (br s,2H), 4.65 (br s, 1H), 7.26-7.36 (m, 5H)

Example 177 Compound 187

In a manner similar to that in Example 15, Compound 187 (90.3 mg, 76%)was obtained from Compound 186 (96.0 mg, 0.269 mmol) prepared in Example176, pyridine (65.4 μL, 0.810 mmol) and pivaloyl chloride (83.4 μL,0.676 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.13 (t, J=6.0 Hz, 3H), 1.28 (s, 9H),2.66 (m, 3H), 2.97 (s, 3H), 3.35 (m, 2H), 3.61 (m, 1H), 4.58 (br s, 1H),7.32 (m, 5H), 8.08 (br s, 1H)

AP-MS (m/z): 441 (M⁺+1)

Example 178 Compound 188

In a manner similar to that in Example 172, Compound 188 (42.5 mg, 45%)was obtained from Compound 186 (100 mg, 0.221 mmol) prepared in Example176, pyridine (85 μL, 1.05 mmol), 4-bromobutyryl chloride (110 μL, 0.949mmol) and potassium carbonate (1.0 g).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.14 (t, J=7.5 Hz, 3H), 2.19 (m, 2H),2.50-2.81 (m, 5H), 2.96 (s, 3H), 3.35 (m, 2H), 3.59 (m, 1H), 3.93 (m,2H), 4.52 (br s, 1H), 7.20-7.34 (m, 5H)

AP-MS (m/z): 424 (M⁻−1)

Example 179 Compound 189

In a manner similar to that in Example 172, Compound 189 (27.6 mg, 37%)was obtained from Compound 186 (60.6 mg, 0.170 mmol) prepared in Example176, pyridine (63.2 μL, 0.788 mmol), 5-bromovaleryl chloride (110 μL,0.949 mmol) and potassium carbonate (1.0 g).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.14 (t, J=7.5 Hz, 3H), 1.79-1.99 (m,4H), 2.54-2.75 (m, 5H), 2.96 (s. 3H), 3.19-3.27 (m, 2H), 3.57-3.68 (m,1H), 3.83-3.95 (m, 2H), 4.36 (br s, 1H), 7.20-7.37 (m, 5H)

AP-MS (m/z): 439 (M⁺+1)

Example 180 Compound 190

In a manner similar to that in of Example 170, Compound 190 (86.5 mg,0.248 mmol) was obtained from Compound 105 (1.01 g, 2.33 mmol) preparedin Example 98 and sodium borohydride (2.20 g, 58.2 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.30 (s, 9H), 2.37-2.46 (m, 1H),2.63-2.86 (m, 2H), 3.41-3.51 (m, 1H), 3.71 (s, 3H), 4.09 (br s, 2H),7.22-7.43 (m, 5H)

Example 181 Compound 191

Compound 191 (89.5 mg, 29%) was obtained in the same manner as that inExample 133 from Compound 190 (86.5 mg, 0.248 mmol) obtained in Example180 and 4-bromobutyryl chloride (57 μL, 0.495 mmol).

AP-MS (m/z): 496 (M⁻−1)

Example 182 Compound 192

Compound 191 (89.5 mg, 0.18 mmol) prepared in Example 181 was dissolvedin N,N-dimethylformamide (2.0 mL). To the solution was added 60% sodiumhydride (14 mg, 0.359 mmol), and the mixture was stirred at roomtemperature for 1 hour. To the reaction mixture was added acetic acidand water, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline, and then dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/n-hexane=2/1) to obtain Compound 192 (30.2 mg, 40%).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.36 (s, 9H), 2.17-2.42 (m, 3H),2.53-2.84 (m, 4H), 3.38-3.50 (s, 1H), 3.72 (s, 3H), 3.97 (m, 2H),7.22-7.39 (m, 5H)

Example 183 Compound 193

In a manner similar to that in Example 99, Compound 193 (21.7mg, 74%)was obtained from Compound 192 (30.2 mg, 0.723 mmol) prepared in Example182 and sodium hydroxide (8.7 mg, 0.217 mmol).

AP-MS (m/z): 402 (M⁻−1)

Example 184 Compound 194

In a manner similar to that in Example 100, Compound 194 (7.3 mg, 30%)was obtained from Compound 193 (21.7 mg, 0.054 mmol) prepared in Example183, oxalyl chloride (0.25 ml) and 2-aminoethanol (16 μL, 26.9 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.17-2.28 (m, 3H),2.54-2.82 (m, 2H), 3.34-3.46(m, 3H), 3.72 (dd, J=4.0, 6.0 Hz, 2H), 3.96(br q, J=7.0 Hz, 2H), 7.32-7.34 (m, 5H)

Example 185 Compound 195

Step 1: In a manner similar to that in Step 1 of Example 1,2-acetoxy-1-indanone=thiosemicarbazone (3.23 g, 57%) was obtained from2-acetoxy-1-indanone (4.1 g, 21.6 mmol) and thiosemicarbazidehydrochloride (3.0 g, 23.7 mmol).

Step 2: In a manner similar to that in Step 2 of Example 1,3-acetyl-6-aminospiro[1,3,4-thiadiazolin-2,1′-indan]-2′-yl acetate(187.4 mg, 48%) was obtained from 2-acetoxy-1-indanone=thiosemicarbazone(335.5 mg, 1.27 mmol) prepared above, pyridine (13 mL) and aceticanhydride (136 μL, 1.53 mmol)

Step 3: 3-Acetyl-5-aminospiro[1,3,4-thiadiazolin-2,1′-indan}-2′-ylacetate (163.8 mg) prepared above was dissolved in dichloromethane (2.0mL). To the solution was added pyridine (520 μL, 6.44 mmol) and pivaloylchloride (661 μL, 5.36 mmol), and the mixture was stirred at roomtemperature for 24 hours. To the reaction mixture was added water andchloroform, and the mixture was extracted with chloroform. The organiclayer was washed with saturated aqueous sodium chloride, and then driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (chloroform/ethyl acetate=3/2) to obtain Compound 195(118.0 mg, 57%) as a diastereoisomer mixture.

AP-MS (m/z): 390 (M⁺+1)

Example 186 Compound 196

Compound 195 (90.3 mg, 0.233 mmol) prepared in Example 185 was dissolvedin methanol solution of 10% ammonia (4.8 mL), and the solution wasallowed to stand at room temperature for 6 hours. The reaction mixturewas concentrated, and then the residue was purified by silica gel columnchromatography (chloroform/ethyl acetate=3/2) to obtain Compound 196(16.6 mg, 20%) as a diastereoisomer mixture.

FAB-MS (m/z): 348 (M⁺+1)

Example 187 Compound 197

Step 1: In a manner similar to that in Step 1 of Example 1,4-acetoxy-1-indanone=thiosemicarbazone (2.78 g, 80%) was obtained from4-acetoxy-1-indanone (2.51 g, 13.2 mmol) and thiosemicarbazidehydrochloride (1.85 g, 14.5 mmol).

Step 2: In a manner similar to that in Example 11, Compound 197 (193.9mg, 39%) was obtained from 4-acetoxy-1-indanone=thiosemicarbazone (364.5mg, 1.38 mmol) prepared above, acetic anhydride (123 μL, 1.38 mmol) andpyridine (112 μL, 1.38 mmol).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 2.18 (s, 3H), 2.30 (s, 3H), 2.59-2.68(m, 1H), 2.76-2.86 (m, 1H), 3.09-3.30 (m, 2H), 4.17 (br s, 2H), 6.99(dd, J=7.7, 1.5 Hz, 1H), 7.31 (m, 2H)

Example 188 Compound 198

In a manner similar to that in Example 15, Compound 198 (136 mg, 98%)was obtained from Compound 197 (108.8 mg, 0.356 mmol) prepared inExample 187, pyridine (346 μL, 4.28 mmol) and pivaloyl chloride (439 μL,3.56 mmol).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.18 (s, 3H), 2.29 (s,3H), 2.56-2.63 (m, 1H), 2.79-2.92 (m, 1H), 3.08-3.22 (m, 2H), 6.98-7.03(m, 1H), 7.28-7.31 (m, 2H), 8.08 (br s, 1H)

Example 189 Compound 199

In a manner similar to that in Example 186, Compound 199 (70.0 mg, 94%)was obtained from Compound 198 (83.1 mg,0.214 mmol) prepared in Example188 and methanol solution of 10% ammonia (4.2 mL).

¹H NMR (300 MHz, CDCl₃) δ (ppm): 1.34 (s, 9H), 2.21 (s, 3H), 2.58-2.67(m, 1H), 2.81-2.91 (m, 1H), 3.07-3.27 (m, 2H), 5.25 (br s, 1H), 6.62 (d,J=7.7 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 7.99 (brs, 1H)

Example 190 Tablets

Tablets comprising the following composition are obtained according tothe conventional method.

Compound 1 5 mg Lactose 60 mg  Potato starch 30 mg  Polyvinyl alcohol 2mg Magnesium stearate 1 mg Tar dye trace

INDUSTRIAL APPLICABILITY

The present invention provides a thiadiazoline derivative or apharmacologically acceptable salt thereof which is useful fortherapeutic treatment of a human malignant tumor, for example, breastcancer, gastric cancer, ovarian cancer, colon cancer, lung cancer, braintumor, laryngeal cancer, hematological cancer, urinary or genital tumorincluding bladder cancer and prostatic cancer, renal cancer, skincarcinoma, hepatic carcinoma, pancreatic cancer, or uterine cancer, orthe like. In addition, the present invention provides an antitumor agentcomprising a thiadiazoline derivative or a pharmacologically acceptablesalt thereof as an active ingredient.

1. A method of treating hematological cancer in a human in need thereofcomprising administering an effective amount of a compound representedby formula (99), (187), (181), (188), (176), or (177),

or a pharmacologically acceptable salt thereof.
 2. The method accordingto claim 1, wherein the compound is a compound represented by formula(176),

or a pharmacologically acceptable salt thereof.